Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Abstract

The progression of immune responses is generally associated with an increase in the overall avidity of antigenspecific T cell populations for peptide-MHC. This is thought to result from preferential expansion of high-avidity clonotypes at the expense of their low-avidity counterparts. Since T cell antigen-receptor genes do not mutate, it is puzzling that high-avidity clonotypes do not predominate from the outset. Here we provide a developmental basis for this phenomenon in the context of autoimmunity. We have carried out comprehensive studies of the diabetogenic CD8 + T cell population that targets residues 206-214 of the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP 206-214 ) and undergoes avidity maturation as disease progresses. We find that the succession of IGRP 206-214 -specific clonotypes with increasing avidities during the progression of islet inflammation to overt diabetes in nonobese diabetic mice is fueled by autoimmune inflammation but opposed by systemic tolerance. As expected, naive high-avidity IGRP 206-214 -specific T cells respond more efficiently to antigen and are significantly more diabetogenic than their intermediate-or low-avidity counterparts. However, central and peripheral tolerance selectively limit the contribution of these high-avidity T cells to the earliest stages of disease without abrogating their ability to progressively accumulate in inflamed islets and kill β cells. These results illustrate the way in which incomplete deletion of autoreactive T cell populations of relatively high avidity can contribute to the development of pathogenic autoimmunity in the periphery. IntroductionThe diversity of the preimmune T and B cell repertoires is accomplished by random rearrangement of large arrays of V, D, and J genes during lymphocyte development. The encoded molecules fold into structures in which 6 hypervariable complementarity-determining regions (CDRs) are brought together to form the receptors' antigen-binding site (1, 2). A key common feature of the antigen-binding site of these receptors is its conformational flexibility, which affords ligand promiscuity (1-11). This degeneracy in antigen recognition is typically associated with low-affinity interactions and is a hallmark of the preimmune B lymphocyte repertoire. It is via the processes of somatic mutation of B cell receptors and selection of antigen-reactivated B cells within germinal centers that B cell responses improve in both their affinity and fidelity for antigen recognition (12-16). This transition is paralleled by dramatic increases in both the association rate of the antigen-binding reaction and the structural rigidity of the receptors' antigen-binding site (9,17).T cell responses usually undergo an analogous process of avidity maturation. Although there is some controversy as to the underlying kinetic mechanisms (i.e., avidity maturation proceeding through or only up to certain avidity thresholds), most studies concur that this process results from competitive survival of c...

The specificity of T cell regulation that enables self-nonself discrimination in the periphery

“…However, while releasing the ''innocent'' self-reactive T cells with low avidity, thymic negative selection also allows a large fraction of self-reactive T cells with intermediate avidity to be released into the periphery under normal circumstances (10)(11)(12). The existence of the intermediate-avidity self-reactive T cells in the periphery represents a potential danger of pathogenic autoimmunity inherited in each individual because these T cells can often be activated when they encounter self-peptides presented at a sufficient level during the adaptive immune response and some may differentiate into potentially pathogenic effector cells to initiate an autoimmune disease (12)(13)(14)(15). We thus postulated that self-nonself discrimination must continue in the periphery after thymic negative selection and one of the major functions of peripheral regulatory mechanisms is to selectively down-regulate immune responses to self-antigens without damaging the normal on going responses to foreign pathogens to maintain self-tolerance (16).…”

Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation

“…Intrathymic deletion of high-avidity, self-reactive T cell clones generates a truncated peripheral self-reactive repertoire composed of mainly intermediate-and low-but devoid of high-avidity clones compared with the foreign-reactive repertoire, which possesses T cells with a full range of avidity. It is likely that potentially pathogenic self-reactive T cells are included in the pool of the ''intermediate-avidity '' thymic escapees that could be activated in the periphery to initiate autoimmune diseases (1)(2)(3)(4). It is thus inevitable that one of the major functions of peripheral regulatory mechanisms is to selectively down-regulate immune response to self-antigens without damaging the ongoing immune response to foreign pathogens (5).…”

Multi-Component Vaccines for Suppression of Type 1 Diabetes

“…Regulation of immunological homeostasis, among the approximate 10 14 commensal microorganisms living on the 10 13 cells of the human body's mucosae requires a delicate balance of activation and suppression of immunity, (Lodinova-Zadnikova et al 2004). The first step in disruption of homeostasis leading to islet-cell mortality is initiated by events that trigger maturation of antigen-presenting cells (APCs), largely dendritic cells (DC), responsible for inducing the morphogenesis of autoreactive CD8+, CD4+ T cells and B cells, which results in the production of anti-beta cell antibodies (Atkinson et al 1994;Han et al 2005;Tisch and McDevitt 1996). The continuous loss of islet -cell function results in a progressive deficiency of insulin production leading to a gradual elevation of blood sugar levels (hyperglycemia), that triggers an increase in cellular oxidative stress leading to chronic inflammation and an associated risk for secondary neural and circulatory pathological complications that include amputation, blindness, kidney failure, heart attack and stroke (Libby et al 2005;Shen and Bornfeldt 2007).…”