Direct antigen presentation by DC shapes the functional CD8⁺ T‐cell repertoire against the nuclear self‐antigen La‐SSB

Abstract

Controversy still surrounds the importance of cross-presentation versus endogenous or direct presentation of MHC-I restricted Ag in CD8 1 T-cell (T CD81 ) immunity. It is even less clear what relative role these pathways play in shaping the T-cell repertoire specific for ubiquitous self-antigens, especially in cases where both Ag presentation pathways could potentially be involved. Here we provide evidence that a T CD81 repertoire specific for a determinant from the nuclear autoantigen La-SSB is largely shaped by direct presentation. In this system, mouse T CD81 reactive to a xenogeneic human La (hLa [51][52][53][54][55][56][57][58] ) K b peptide did not recognize directly presented peptide on either spleen cells from hLa-Tg mice or hLa transfected syngeneic cells. Interestingly, the same T CD81 were activated by in vivo challenge with allogeneic APC expressing either the Tg hLa or loaded with intact recombinant hLa protein, indicating functional cross-presentation of the hLa [51][52][53][54][55][56][57][58] . However, in irradiated bone marrow chimeric mice, DC expressing Tg hLa, but not WT DC that matured in hLa-Tg mice, constitutively presented the hLa [51][52][53][54][55][56][57][58] to T CD81 . These data demonstrate that although both the direct-and cross-presentation pathways are potentially operative in revealing hLa [51][52][53][54][55][56][57][58] to T CD81 , the T CD81 repertoire to this determinant is shaped quantitatively according to the efficiency of Ag presentation.Key words: Antigen processing/presentation . Autoimmunity . T-cell repertoire IntroductionAutoimmunity to nuclear antigens, in particular components of ribonucleoprotein complexes, is common in systemic autoimmune syndromes such as systemic lupus erythematosus and primary Sjögren's syndrome [1]. However, the mechanisms that shape the T-cell repertoire to these proteins and the role these auto-reactive T cells play in disease pathology are not well understood. Poor self-tolerance of some nuclear/cytoplasmic proteins and a propensity for them to become autoimmune targets could result from their sequestered localization [2], their low abundance or rapid turnover [3], and their exposure to antibodies during redistribution and concentration in apoptotic blebs [4]. Further, their association with RNA and the potential to stimulate TLR7 and 8 [5], coupled with defects in apoptosis and clearance of debris, renders some nuclear Ag as clinically relevant targets of autoimmunity [6,7]. Although much of the pathology in systemic autoimmunity is due to the deposition of complement-fixing immune complexes [8], CD81 T cells (T CD81 ) have increasingly been implicated in other autoimmune conditions [9,10]. However, the functional T CD81 repertoire specific to such nuclear autoantigens and the mode of MHC-I restricted antigen 330presentation (direct-versus cross-presentation) during the establishment of such T CD81 repertoire have not been investigated.The T CD81 repertoire is shaped by MHC-I restricted antigens presented on APC both in the thymus and...

Absence of CD4+ T cell help generates corrupt CD8+ effector T cells in sarcoma-bearing Swiss mice treated with NLGP vaccine

“…Cytotoxic function of CD8 + T cells is related to quality of antigen presentation [39]. NLGP in tumor condition optimized the antigen presentation by DCs [26] and macrophages [40] by switching of indoleamine 2, 3-dioxygenase (IDO) secreting DC2 to DC1 [26,40,41].…”

Innate Immune Responses in Fish: Antigen Presenting Cells and Professional Phagocytes

“…Following antigen processing, APCs present peptides by major histocompatibility complex (MHC) molecules (Drutman & Trombetta, 2010). For example, intracellular antigens are presented by MHC class I molecules to cytotoxic T cells (CD8+ T cells), while extracellular antigens are presented by MHC class I molecules to helper T cells (CD4+ T cells) (Keech, Pang, McCluskey, & Chen, 2010;Vyas, Van der Veen, & Ploegh, 2008) (Figure 2). Upon activation, another critical feature of APCs is the expression of co-stimulatory molecules, such as B7-1 (CD80), and B7-2 (CD86), which are necessary to prime naïve T cells and induce the differentiation of T cells by producing cytokines (Chen & Flies, 2013).…”

Highly tailorable gellan gum nanoparticles as a platform for the development of T cell activator systems

“…One such novel methodology is artificial antigen presentation which has emerged as a very promising concept due to its versatility both in terms of the platform used to build the system and the T cell activation method adopted. Over the past decades, several artificial antigen presenting cells (aAPCs) based on distinct systems have been developed with promising results in the in vivo expansion of specific T cells [10][11][12] with further evidence provided when applied to more advanced disease models of murine experimental autoimmune encephalomyelitis, collagen induced arthritis, non-obese diabetic animals [13] and cancer [14]. The base architecture of these systems has relied on the use of iron oxide nanoparticles [13], synthetic polymers [11], liposomes [15], magnetic beads [10,14,16] and cell engineering methodologies [12,17,18].…”

“…Over the past decades, several artificial antigen presenting cells (aAPCs) based on distinct systems have been developed with promising results in the in vivo expansion of specific T cells [10][11][12] with further evidence provided when applied to more advanced disease models of murine experimental autoimmune encephalomyelitis, collagen induced arthritis, non-obese diabetic animals [13] and cancer [14]. The base architecture of these systems has relied on the use of iron oxide nanoparticles [13], synthetic polymers [11], liposomes [15], magnetic beads [10,14,16] and cell engineering methodologies [12,17,18]. However, one of the greatest handicaps of these systems is the difficulty in generating, within a short period of time, large numbers of modified T cells of a defined phenotype and with a specified ratio of subsets [19].…”