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Diversity & overlap in the mechanisms of processing protein antigens for presentation to T cells

Article in The Indian Journal of Medical Research · September 2004

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Diversity & overlap in the mechanisms of processing protein antigens for presentation to T cells

Deepa Rajagopal, Vineeta Bal, Anna George & Satyajit Rath National Institute of Immunology, New Delhi, India

Received February 23, 2004 The immune system needs to recognise target protein antigens from pathogens residing in both extracellular and intracellular locations. Intricate proteolytic processing events that follow antigen/ pathogen encounter provide the immune system with a complex display of a heterogeneous peptide mix, instrumental in the initiation of T cell immune responses, and allow the separation of extracellular and intracellular pathogen identification. However, recent evidence shows that this conventional dimorphism in the proteolytic processing of endogenous versus internalised antigen is less restrictive than originally recognized. The events that constitute the conventional major histocompatibility complex (MHC)-restricted processing pathways are accompanied by interesting deviations that provide novel adjuncts for the processing machinery to gain access to antigen in varied intracellular locations. This review discusses these aspects of classical and non-classical processing pathways for MHC-restricted protein presentation, which play significant roles in both optimising and diversifying the peptide repertoire available for immune recognition. Key words Antigen processing and presentation - endogenous antigen - exogenous antigen - MHC class I - MHC class II - proteasome

Review Article

Indian J Med Res 120, August 2004, pp 75-85

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Antigen processing and presentation pathways are central to generation of immune responses1. The immune system encounters substances either present in the external milieu, like bacteria, protein antigens, toxins, or harboured internally such as viruses, endogenous products etc. The crucial immune functions that direct and co-ordinate the delivery of the pathogen/antigen for immune recognition and subsequent generation of T cell responses have been recognized as components of antigen presentation pathways. These functions begin with proteins at various subcellular locations in the antigen presenting cell (APC), and end with the expression of a peptide-loaded major histocompatibility complex (MHC) molecule on the APC surface, which can be recognised by T cells of the appropriate specificity. While there are growing indications that non-peptidic antigens are also efficiently processed and presented to T cells, this review will concentrate on the handling of protein antigens. The MHC class I (MHC I) molecular complex consists of the highly polymorhpic integral membrane glycosylated α-chain, non-covalently associated with β-2 microglobulin (β2m)2. MHC class II (MHC II) molecules are heterodimeric complexes of non-covalently associated α and β chains3. The key features of both classes of MHC molecules permit diversity in the recognition of a variety of ligands and distinguish the subsets of T cells they activate. The immune system has evolved parallel systems of protection against different kinds of infections. Protection against viral infections or tumours requires destruction

• f the infected or aberrant cell and the MHC I-restricted

cytotoxic CD8 T cells can restrict viral infections or confer immunity to tumours by lysis of infected cells and tumours. On the other hand, bacterial pathogens confronted by phagocytic cells are recognized by MHC II-restricted CD4 T cell responses, which either serve to secrete cytokines and help enhancement of other arms of the immune system such as the humoral responses culminating in clearance of bacterial infections4,5.

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INDIAN J MED RES, AUGUST 2004

Therefore, different antigens need to be presented

• n either MHC I or MHC II for efficient effector

immunity to be generated. The binary notion of antigen presentation holds that endogenous antigens are processed and presented in the context of MHC I, while exogenous antigens processed endosomally typically associate with MHC II6. Despite this apparent segregation of the processing pathways, an increasing body of evidence suggests that in fact exogenous antigens do gain access to the MHC I pathway7,8 and also that antigenic peptides derived from cytosolic sources of antigen are presented in the context of MHC II9,10. Antigen presenting cell types MHC I expression is prevalent on all nucleated cells; a feature that permits a crucial role of CD8 T cells in the control of systemic virus infections through MHC I- restricted presentation. MHC II expression is restricted to certain cell types like B-cells, dendritic cells (DC) and macrophages, which are specialized in the stimulation

• f T cells and immune regulation and thus referred to as

“professional” antigen presenting cells. Based on the ability to process and present bacterial derived peptides

• n MHC I11 and support super-antigen mediated T cell

activation, the role of polymorphonuclear neutrophils (PMN) as APCs, although in restricted situations, is beginning to be recognized12,13. The MHC I restricted presentation pathway The MHC I presentation pathway has evolved to permit CD8 cells to sample protein content of the cell in the form of antigenic peptides bound to MHC I14. The MHC I presentation machinery requires the bridging together of components spatially segregated in distinct sub-cellular locations: (i) Peptide ligands generated as products of proteolytic degradation in the cytosol, and (ii) MHC molecules that load peptides in the endoplasmic reticulum (ER). Cytosolically generated peptides are transferred to the ER via an ATP-dependent, transporter associated with antigen processing; TAP, for binding to MHC I15. Tapasin as a part of the loading complex maintains antigenic peptides released by TAP in the vicinity of peptide receptive MHC I16. Once loaded, peptide-MHC complexes are transported to the cell surface for recognition by the cytotoxic T-lymphocytes. Nature of antigenic precursors The antigenic peptides generated within the cell though diverse in sequence are precisely designed to bind highly polymorphic MHC I molecules. The nature of precursors for antigenic peptides in vivo has been intriguing. While

• n one hand it has been envisaged that peptides for

MHC I binding might be a by-product of normal protein turnover useful in immune recognition, there is evidence to suggest that nascent, aberrant polypeptides generated as a consequence of error prone translations mechanisms in the cell serve as important antigenic precursors in vivo17,18. The diverse peptide pools generated through constitutive proteolytic mechanisms on these distinct sets

• f cellular substrates form an important primary source
• f ligands for MHC I binding. The ubiquitin-proteasome,

the principal pathway for protein turnover in eukaryotes is a major system for generation of peptides for the MHC I

• pathway19. Several factors determine susceptibility to

protein degradation and consequently the nature of peptides generated for MHC binding. Proteins with PEST (Pro, Glu, Ser, Thr) sequences are shown to undergo rapid degradation20. The N-terminal residues have also been shown to impact susceptibility to degradation as described by the N-end rule21. Proteins conjugated to ubiquitin are predominantly targeted to the proteasome, though ubiquitin independent modes of substrate recognition also exist within the cell22. Besides constitutive turnover of “ageing” proteins as providing a source for antigenic peptide generation, nascent products of protein synthesis have increasingly been implicated as significant contributors to the peptide

• pool. Stringent quality control mechanisms in the cell

monitor the formation of mis-folded, incomplete or aberrant products of translation. It has been estimated that a large fraction, approximately 18-55 per cent of the newly synthesized proteins is rapidly degraded in a variety of primary cell lines including DC and

• macrophages. While this degradation translates to about

11 per cent loss in cellular energy, such defective ribosomal products, DRiPs, serve as an important source

• f antigenic peptides for MHC binding23,24. An evaluation
• f the quantitative aspects of protein synthesis and

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degradation reveals interesting facets critical to the efficiency of MHC-peptide complex generation25. It is estimated that on an average 2.6x109 proteins per cell undergo degradation at the rate of 1.8x106 substrates per minute. The productive formation of a single MHC I-peptide complex follows the loss of as many as 450-3000 substrates by degradation26. Studies point out to two important facts: First, that majority of peptides formed in the cytosol are destroyed prior to MHC association and only a very minor proportion of peptides actually survive to become ligands for MHC I binding. Secondly, the overall outcome of endogenous antigen processing events is a critical balance between protein synthesis and cellular mechanisms for protein degradation. Thus antigenic peptides seem to be generated from two distinct pools of polypeptides- full length mature proteins, which are targets for inherent protein degradation mechanisms and more importantly, newly synthesized partial by-products of erroneous protein translation subject to degradation. The relative contribution of the two diverse precursor pools to antigenic peptide supply is still unclear. Cryptic translation: an auxiliary antigenic peptide source Peptides generated either from initiation at unconventional codons giving rise to alternate reading frames, or products of translation of intronic sequences, flanking untranslated regions in the primary transcript serve as a novel addendum to the diversity of peptides for scanning by the cytotoxic T lymphocyte (CTL)27. Though several examples of cryptic translation have been described in murine models with viral infections like vaccinia virus, MMLV-derived retrovirus etc.28, products arising from intronic sequences in genes of certain human melanomas and cancers29, it is unclear as to what proportion of peptides are likely to be derived from this

• source. It has recently been shown that these processes

might occur constitutively in normal circumstances as well and thereby could contribute relatively to the overall peptide repertoire30. Stringency in peptide length requirement for MHCI peptide binding Typically, ligands for MHC I binding are octamer/ nonamer sequences with a consensus motif specifying MHC and T cell receptor contact sites. Distinct proteolytic events in the MHC I processing pathway work with a great degree of precision to generate the exact –COOH and –NH2 termini of MHC I bound

• peptides. Evidence against a C-terminal carboxypeptidase

activity in the ER31, favours the notion that cytosolic proteases/proteasomes can generate peptides with the correct carboxy termini. The resultant peptides however, carry amino terminal extensions, which require further action of cytosolic or ER- amino peptidases to generate the correct peptide for MHC I binding. Most peptides released by the proteasomes into the cytosol form ready substrates for complete degradation by cytosolic amino

• peptidases. The peptides that survive are channeled

through TAP, via an energy dependent process. The ER resident amino terminal trimming activity recently identified as ER-amino peptidase 1 (ERAP 1) has been shown to impact antigen presentation32,33. Under basal conditions ERAP 1 has been shown to limit antigen presentation by trimming precursor peptides to below the optimal size such that only the perfectly binding peptides escape destruction. It has been speculated that either the MHC molecule itself acts as a scaffold for bound peptide to be accessible for amino peptidase action,

• r multiple rounds of peptide-binding and dissociation that

may ensue to ascertain the “best fit”, permit amino peptidase action (Fig.1). Particularly significant is the induction of ERAP1 by interferon-gamma (IFN-γ)34. Cytokines like IFN-γ produced during inflammation induce the replacement of the constitutive proteasomes by alternate subunits like low molecular weight proteins 2/7 (LMP2/7) and multi-catalytic endopeptidase complex like, MECL1 and lead to the assembly of immuno-proteasomes35. Associations such as these alter proteolytic potential of the proteasome and either serve to reduce the susceptibility of peptides to degradative mechanisms that might otherwise destroy a nominal MHC I binding peptide or result in the generation

• f a novel set of peptides, which are qualitatively or

quantitatively different compared to peptides generated through the constitutive proteasomes. Qualitative changes induced in the components of antigen processing elements in the face of infections may thus influence the repertoire

• f peptides available for presentation to the immune system

and aid in immune surveillance.

RAJAGOPAL et al : RECENT CONCEPTS IN ANTIGEN PROCESSING MECHANISMS

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Exogenous antigens in the MHC I pathway Early experiments have demonstrated that mice immunized with cells expressing the foreign minor histocompatibility antigens mount a MHC I restricted response to the antigen in the context of self-MHC, a pathway referred to as “cross-presentation”36. Thus acquisition of antigen by APC from exogenous sources, such as those derived from virus infected donor cells could be important for the induction of MHC I-restricted CD8 T cell responses. The APC capable of mediating cross priming in vivo have recently been identified as the CD8 ∝ DC37. Data from several groups independently define cross-presentation to be sensitive to proteasome inhibitors and dependent on TAP function38,39. Further the presentation through this pathway is sensitive to brefeldin-A, a fungal metabolite that blocks egress from the ER40. Taken together these observations point out that the cytosol is the focal point for peptide generation and peptide loading occurs in the ER, a process that requires TAP-mediated transport of cytosolically generated peptides to the ER. How does one reconcile to the convergence of antigen in a distinct topological pocket with the degradation machinery in the cytosol? A resolution to this apparent paradox comes from recent findings demonstrating ER-phagosome fusion shortly following pathogen engulfment, a process resulting in transfer of ER machinery to the phagosome

• membranes. Particularly significant is the observation

that the phagosome inherits the ER-resident, Sec61 complex41, known to be involved in the transport to and export of proteins from the ER. This complex might be instrumental in the export of oligopeptides generated in the phagosome gain access to the membrane- associated/membrane-proximal proteasomes. Further transport of proteasome-generated peptides is perhaps TAP-mediated, another complex the phagosome membrane inherits from the ER. The model proposed supports the contention of phagosome to cytosol delivery of endocytosed antigen, followed by cytosolic

• Fig. 1. Pathway for MHC class I restricted presentation of cytosolic antigen. Cytosolic/endogenous antigen is degraded in the cytosol

predominantly by the proteasome. Most peptides generated, however, are degraded by cytosolic aminopeptidases and oligopeptidases like

• TOP. Those that survive are transported to the ER by TAP. Peptides generated by proteasome have the correct C-terminus, but bear N-terminal
• extensions. Processive action of ER-resident aminopeptidase, ERAP1, generates the proper amino terminus and the assembled peptide MHC

complexes transit to the cell surface for T cell recognition. INDIAN J MED RES, AUGUST 2004

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degradation and TAP mediated transfer back to the phagosome for MHC I loading (Fig. 2A). Thus early fusion events render the phagosome to a novel, self- contained, antigen-processing compartment42. A fundamentally different pathway for MHC I- restricted presentation of exogenous antigens is also

• perative. Proteins/antigens targeted to the scavenger

receptors through modification by maleylation are presented efficiently through the MHC I pathway. The process is sensitive to agents like ammonium chloride known to disrupt endolysosomal acidification, suggesting that the internalized antigen is processed endosomally and that peptide is loaded independent of TAP43. Additionally maleyl ovalbumin delivered to the cytosol is very poorly presented. Maleylation at the lysine residues, might make the protein a poor target for ubiquitination and in turn, proteasome degradation, a possibility supported by the inability of maleyl ovalbumin loaded splenocytes to prime a CTL response in vivo. Stable MHC I peptide complexes from the cell surface have been shown to recycle to the endocytic compartments. Peptide dissociation at low pH in the endolysosomal compartments can lead to the generation of empty MHCI peptide molecules that could be re-loaded with fresh

• peptides44. Important distinctions in receptor mediated

antigen uptake versus phagocytosis might thus reflect upon the intracellular handling of the antigen (Fig. 2B). The MHC II pathway for antigen presentation MHC II molecules transit to the exocytic compartments consorted by the mono-morphic invariant chain (Ii), following biosynthesis45,46.

• Fig. 2. Pathways for MHC class I restricted presentation of exogenous antigen. A. Exogenous antigen that enters the MHC class I pathway

following phagocytosis takes a TAP-dependent pathway for presentation on MHC class I. ER-phagosome fusion that follows leads to the transfer of ER machinery like TAP, Sec 61 complexes and MHC class I to the phagosome. Relatively large pathogen derived precursor peptides (PDP) are transported to the cytosol, a process probably mediated by the ER-derived Sec61 complex. Proteasomal degradation follows and the peptides generated re-enter the phagosome through TAP. The MHC class I peptide complexes assembled, transit to the cell surface to recognition by the T cell. B. Receptor mediated endocytic uptake can also target antigen to the class I presentation pathway. This pathway for loading is TAP-independent and endosomal and thus could rely on the recycling MHC class I. These class I molecules could be re-loaded with peptides generated in the endosomal compartments and subsequently peptide loaded class I MHC complexes are transported to the cell surface for T cell recognition. However, the mechanisms that generate the optimal length peptide with proper C and N-terminus are not clearly understood. RAJAGOPAL et al : RECENT CONCEPTS IN ANTIGEN PROCESSING MECHANISMS

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Endolysosomal resident proteases, cathepsins, then proteolytically cleave the invariant chain; leaving a MHC II associated invariant chain peptide, CLIP in the peptide-binding groove. Efficient loading of antigenic peptide requires CLIP release. While the acidic environment in the endolysosomal compartments permits CLIP removal to some extent, peptide exchange is facilitated by the MHC II region encoded chaperone, HLA-DM (DM)-in humans or H-2M in mice47. DM mediated peptide exchange follows classical Michelis Menton kinetics and 3-12 MHC II molecules are loaded with peptide by one DM molecule48. While the DM molecule lacks the ability of direct peptide binding, it regulates the binding stringency by stabilizing a conformation of the MHC II groove that allows the predominant association of high affinity peptides. Dichotomy in MHC II antigen presentation The generation and loading of peptides on MHC II is diversified, since two cohorts of MHC II molecules have been recognized. The nascent molecules that encounter peptides in the late endosomal-lysosomal compartments constitute the classical pathway of peptide presentation

• n MHC II. Recycling MHC II molecules that encounter

peptides in the transferrin receptor positive early endosomal vesicles mediate a minor alternate pathway49 (Fig.3A). Unlike MHC I beset with stringent requirements for the optimal peptide length, MHC II is permissive to interaction with longer oligopeptides due to the open- ended structure of the peptide-binding groove. The low

• Fig. 3. Pathways for presentation of exogenous vs. cytosolic antigen on MHC class II. A. The classical pathway for presentation of exogenous

antigen on MHC class II follows internalization of antigen by phagocytosis. Relatively large polypeptide pathogen derived precursor peptides are generated and form a substrate for endolysosomal proteinases, cathepsins, which function optimally in the acidic pH environment. Peptides generated by endolysosomal cleavage bind MHC class II molecules that reach the location either by recycling from the plasma membrane or from the ER, through the golgi, bound by the invariant chain. The MHC class II peptide complexes thus assembled, are translocated to the plasma membrane for T- cell recognition. B. Antigen from cytosolic sources is degraded by both the proteasome and other non- proteasomal cytosolic degradation machinery. Peptides generated are transported to the ER presumably by members of the ATP-binding cassette (ABC) family of transporters where they are loaded predominantly on nascent MHC class II molecules. Peptide MHC complexes transit to the cell surface following peptide loading. INDIAN J MED RES, AUGUST 2004

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pH-induced conformational changes in the early endosomal compartments permit MHC II binding of relatively large peptides50,51 and consequently epitopes presented on nascent versus recycling MHC II require distinct endosomal functions. The significance of the minor recycling pathway is not very well understood. However, it may be envisaged that such mechanisms for peptide loading might serve to broaden the plethora of peptides sampled and ensure the survival of peptides that are made available in less acidic and proteolytic early endosomal environments and perhaps susceptible to complete degradation in the classical late endocytic pathway. Conceivably such a pathway would be independent of DM function for loading, though inherent cell biological properties of the cell such as rates of phagocytosis might have a bearing. Unpublished data from our lab show that presentation

• f a protein in the cytosol is sensitive the protein synthesis

inhibitors like cycloheximide, while presentation of antigen following exogenous uptake does not depend on new protein synthesis. Therefore it is likely that endogenous MHC II-restricted antigen presentation

• ccurs on newly synthesized MHC II, while peptides

generated following exogenous fluid phase uptake would be presented on recycling MHC-II. MHC II restricted antigen presentation of cytosolic antigens Recent reports indicating the ability of MHC II to present peptides derived from cytosolic or endogenously derived antigens have added a new dimension to our understanding of antigen presentation pathways (Fig.3B). Proteasomal and non-proteasomal cytosolic proteases have been shown to be pertinent to peptide generation in the MHC II pathway52,53. Contrast to the MHC I pathway, the MHC II pathway

• f loading has been found to be independent of the

ER-resident, ATP-binding cassette containing transporter, TAP54,55. Although a direct physical association of the proteasome with TAP has not been demonstrated, peptides generated through proteasome are presumably channelled to the ER via TAP for loading on MHC I. APC from TAP knock out mice (deficient in the MHC I-restricted presentation of cytosolically generated peptides) are proficient in MHC II presentation of antigens of cytosolic origin. Thus alternate transport mechanisms by which cytosolically generated peptides are transported for loading on MHC II maybe envisaged. Sulfonamide drugs like glybenclamide that inhibit the anion exchange function of the ATP-binding cassette, ABC transporter family members, ABC1, were found to inhibit MHC II presentation of cytosolic or endogenous antigens, suggesting a possible role of alternate ABC family or the like transporter families (unpublished data). Proteases in the MHC II pathway Antigenic proteins need to be converted proteolytically to generate ligands for MHC II binding. However, proteolysis in the MHC II pathway has a more basic function and is a pre-requisite for the generation of peptide receptive MHC II. As discussed earlier, MHC II αβ dimers associated in the ER are protected at the peptide-binding site by the invariant chain derived, CLIP peptide; and restoration of the peptide binding capacity requires CLIP release. Exposure to acidic pH initiates unfolding of several

• proteins. Denaturation of proteins is brought about by

the gamma-IFN inducible lysosomal thiol reductase, GILT, an enzyme capable of disulfide bond reduction at low

• pH56. Asparagine endopeptidase (AEP) or mammalian

legumain, an asparagine-specific cysteine protease shown to initiate processing of carboxy terminal of tetanus toxin antigen in B-cells, has been implicated in the initial steps of Ii processing57,58. Following initial steps of cleavage, the protein antigen becomes accessible to a wide range of endosome resident proteases. The endolysosomal proteases, catB and catD were the first set of cathepsin (cysteine/aspartate protease) family enzymes to be described as essential players in the MHC II pathway59. However, catB or catD deficient APC showed presentation profiles comparable to the wild type counterparts, suggesting that alternate proteases might functionally compensate for the deficit. Ii cleavage in the thymic epithelial cells is mediated by catL60. Another cysteine protease expressed in catS, has been ascribed a more prominent role in endolysosomal function. The protease is up-regulated by IFN-γ. The phenotype of catS null mice revealed APC subtype specific differences in protease usage. Macrophages were functionally found normal, while initial stages of B-cell responses were normal, catS null mice were more deficient in secreting

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certain isotypes such as IgG2 and IgG361. Both catS and catL KO mice display defects in invariant chain proteolysis. The proteolytic events involved in the MHC II pathway, thus seem to overlap between two crucial functions-those that degrade Ii to generate MHC II molecules capable of binding peptide, and those generating ligands for MHC II binding. The functional redundancy as evident from the various protease KO mice phenotypes suggests the existence of a combination

• f proteases with overlapping specificities helps ensure

the efficiency of the CD4 T cell response in a varied scenario. Chaperones in presentation pathways Mechanisms that maintain quality control in the cell is mediated by molecular chaperones, a group of highly conserved proteins that co-ordinate multitudinous cellular processes, most importantly regulation of protein folding and degradation balances in the cell. In coherence with the general chaperoning functions, heat shock proteins, hsp70 and hsp90 families have been suggested as chaperones for antigenic peptides62. Peptides released into the cytosol are degraded by cytosolic proteases like thimet oligopeptidase63, unless rescued by TAP for

• transport. Inhibition of the proteasome activity with

lactacystin restores presentation of cytosolically loaded

• valumin derived, Kb-restricted, SIINFEKL peptide in

TAP deficient APCs (unpublished observations). During its sojourn to the ER two opposing forces determine the fate of an antigenic peptide: peptide generation by proteasome and mechanisms that protect the peptide from proteolytic degradation in the cytosol. Group II chaperonin, tailless complex polypeptide1 (TCP1) ring complex, TRiC has been shown to protect proteolytic intermediates in the MHC I pathway from proteases in the cytosol64. Our unpublished results implicate the role

• f hsp90 chaperone family in the MHC II antigen

presentation pathway, adding another element to the increasingly apparent functional link of the heat shock protein family members with the immune system. Discussion The immune system utilizes generalized catabolic processes and transport mechanisms within the cell to carry out the very basic function of proteolysis and transport of antigenic peptides. This highlights an important concept of basic cell biological phenomena with overlapping functions in the immune system. The phenomenon however seems enigmatic in that although the processing machinery seems conserved, there is still uniqueness in individual responses related with differential susceptibilities to disease and infections. Similarly though all MHC I molecules bind nonamer peptides, the peptide sequences and binding specificities vary tremendously such that from the identical “proteome” in the cell, numerous sets of highly variant peptides are generated. These features suggest the influence of MHC molecules in shaping the peptide

• repertoire65. Our understanding of MHC-template driven

processing of extended proteolytic intermediates in the ER further invokes the active role of MHC molecules, in modulating the outcome of antigen processing events

• ccurring distally in the cytosol66.

Similarly basic cellular phenomena govern the generation of ligands for MHC II binding. Mechanisms for antigen uptake and internalization are diverse and tightly regulated. Receptor mediated endocytosis, fluid phase or phagocytic uptake primarily serve to concentrate ligands intracellularly into compartments competent for antigen processing and presentation. The basic cell biological properties of antigen presenting cell dictates the endocytic compartments to which the antigen would be targeted. These factors facilitate a productive immune response. Although a dichotomy of antigen presentation pathways has been envisaged, it is becoming exceedingly clear that criss-cross pathways also prevail. As with other biological phenomena, there seems significant redundancy in the classical and non-classical pathways and probably vital issues such as form, identity of antigen, intracellular localization in professional versus non-professional APC, determines the pathway chosen. While the extent of contribution of alternate pathways such as cross priming in vivo is debatable67, such pathways translate into broadening the spectrum of antigens gaining access to varied antigen processing pathways. Finally, the role of heat shock family as chaperones for antigenic peptides in the cytosol and endosomal

INDIAN J MED RES, AUGUST 2004

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compartments add to conjunction of cellular housekeeping elements with functions in an array of immunological phenomena. The immune system modifies the basic profile extensively and to its advantage by immunomodulatory cytokines. In summary, nature’s elegant way of effective immune surveillance through antigen-processing pathways can be considered as modified operations and outcomes of the basic biology

• f the cell.

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