Diversity & overlap in the mechanisms of processing protein - PDF document

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/8365216 Diversity & overlap in the mechanisms of processing protein antigens for presentation to T cells Article in The Indian Journal of Medical Research · September 2004 Source: PubMed CITATIONS READS 3 126 4 authors , including: Deepa Rajagopal Vineeta Bal Imperial College London National Institute of Immunology 18 PUBLICATIONS 653 CITATIONS 162 PUBLICATIONS 3,268 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Tlr7 innate immunity View project All content following this page was uploaded by Deepa Rajagopal on 20 May 2014. The user has requested enhancement of the downloaded file.

Review Article Indian J Med Res 120, August 2004, pp 75-85 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 glycosylated α -chain, non-covalently associated with Antigen processing and presentation pathways are β -2 microglobulin ( β 2m) 2 . MHC class II (MHC II) central to generation of immune responses 1 . The immune system encounters substances either present in the molecules are heterodimeric complexes of non-covalently associated α and β chains 3 . The key features of both external milieu, like bacteria, protein antigens, toxins, or harboured internally such as viruses, endogenous classes of MHC molecules permit diversity in the products etc . The crucial immune functions that direct recognition of a variety of ligands and distinguish the and co-ordinate the delivery of the pathogen/antigen for subsets of T cells they activate. immune recognition and subsequent generation of T cell responses have been recognized as components of The immune system has evolved parallel systems of antigen presentation pathways. These functions begin protection against different kinds of infections. Protection with proteins at various subcellular locations in the antigen against viral infections or tumours requires destruction presenting cell (APC), and end with the expression of a of the infected or aberrant cell and the MHC I-restricted peptide-loaded major histocompatibility complex (MHC) cytotoxic CD8 T cells can restrict viral infections or molecule on the APC surface, which can be recognised confer immunity to tumours by lysis of infected cells by T cells of the appropriate specificity. While there are and tumours. On the other hand, bacterial pathogens growing indications that non-peptidic antigens are also confronted by phagocytic cells are recognized by efficiently processed and presented to T cells, this review MHC II-restricted CD4 T cell responses, which either will concentrate on the handling of protein antigens. serve to secrete cytokines and help enhancement of other arms of the immune system such as the humoral responses The MHC class I (MHC I) molecular complex consists of the highly polymorhpic integral membrane culminating in clearance of bacterial infections 4,5 . 75

76 INDIAN J MED RES, AUGUST 2004 receptive MHC I 16 . Once loaded, peptide-MHC Therefore, different antigens need to be presented on either MHC I or MHC II for efficient effector complexes are transported to the cell surface for immunity to be generated. The binary notion of antigen recognition by the cytotoxic T-lymphocytes. presentation holds that endogenous antigens are processed and presented in the context of MHC I, while Nature of antigenic precursors exogenous antigens processed endosomally typically associate with MHC II 6 . Despite this apparent The antigenic peptides generated within the cell though segregation of the processing pathways, an increasing diverse in sequence are precisely designed to bind highly body of evidence suggests that in fact exogenous antigens polymorphic MHC I molecules. The nature of precursors do gain access to the MHC I pathway 7,8 and also that for antigenic peptides in vivo has been intriguing. While antigenic peptides derived from cytosolic sources of on one hand it has been envisaged that peptides for antigen are presented in the context of MHC II 9,10 . MHC I binding might be a by-product of normal protein turnover useful in immune recognition, there is evidence Antigen presenting cell types to suggest that nascent, aberrant polypeptides generated as a consequence of error prone translations mechanisms MHC I expression is prevalent on all nucleated cells; in the cell serve as important antigenic precursors a feature that permits a crucial role of CD8 T cells in in vivo 17,18 . The diverse peptide pools generated through the control of systemic virus infections through MHC I- constitutive proteolytic mechanisms on these distinct sets restricted presentation. MHC II expression is restricted of cellular substrates form an important primary source to certain cell types like B-cells, dendritic cells (DC) of ligands for MHC I binding. The ubiquitin-proteasome, and macrophages, which are specialized in the stimulation the principal pathway for protein turnover in eukaryotes of T cells and immune regulation and thus referred to as is a major system for generation of peptides for the MHC I “professional” antigen presenting cells. Based on the pathway 19 . Several factors determine susceptibility to ability to process and present bacterial derived peptides protein degradation and consequently the nature of on MHC I 11 and support super-antigen mediated T cell peptides generated for MHC binding. Proteins with PEST activation, the role of polymorphonuclear neutrophils (Pro, Glu, Ser, Thr) sequences are shown to undergo (PMN) as APCs, although in restricted situations, is rapid degradation 20 . The N-terminal residues have also beginning to be recognized 12,13 . been shown to impact susceptibility to degradation as described by the N-end rule 21 . Proteins conjugated to The MHC I restricted presentation pathway ubiquitin are predominantly targeted to the proteasome, though ubiquitin independent modes of substrate The MHC I presentation pathway has evolved to recognition also exist within the cell 22 . permit CD8 cells to sample protein content of the cell in the form of antigenic peptides bound to MHC I 14 . The Besides constitutive turnover of “ageing” proteins as MHC I presentation machinery requires the bridging providing a source for antigenic peptide generation, together of components spatially segregated in distinct nascent products of protein synthesis have increasingly sub-cellular locations: been implicated as significant contributors to the peptide pool. Stringent quality control mechanisms in the cell ( i ) Peptide ligands generated as products of monitor the formation of mis-folded, incomplete or proteolytic degradation in the cytosol, and aberrant products of translation. It has been estimated that a large fraction, approximately 18-55 per cent of ( ii ) MHC molecules that load peptides in the the newly synthesized proteins is rapidly degraded in a endoplasmic reticulum (ER). variety of primary cell lines including DC and macrophages. While this degradation translates to about Cytosolically generated peptides are transferred to the 11 per cent loss in cellular energy, such defective ER via an ATP-dependent, transporter associated with antigen processing; TAP, for binding to MHC I 15 . Tapasin ribosomal products, DRiPs, serve as an important source of antigenic peptides for MHC binding 23,24 . An evaluation as a part of the loading complex maintains antigenic peptides released by TAP in the vicinity of peptide of the quantitative aspects of protein synthesis and