Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

Abstract

Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a selfspecific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.autoimmunity | AIRE | transgenic mouse

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…These observations are consistent with the hypothesis that the increased sensitivity of memory T cells to elaborate effector function has to be balanced with tight control in order to limit their pathogenicity. Increased antigen threshold requirements have been reported for memory CD4 + and CD8 + T cells, resulting in preferential proliferation of naive T cells over memory cells (46)(47)(48)(49)(50). Thus, it is possible that the proliferation observed in our presensitized mice following B/c heart transplantation was actually driven predominantly by naive cells rather than by memory T cells, thereby explaining our observation that CTLA4-Ig inhibited donor-specific T cell expansion in sensitized recipients.…”

Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens

“…S1e ). KLRG1 expression, related to terminally differentiated CD8+ T cells and senescence 22 23 , and expression of CD127 (IL-7R), which is associated with memory phenotypes and downregulation of which has been linked to deletional tolerance, were also measured 21 . Expression of both CD127 and KLRG1 were significantly lower in response to erythrocyte-targeted versus soluble antigens ( Fig.…”

TCR stimulation without co-stimulatory signals induces expression of “tolerogenic” genes in memory CD4 T cells but does not compromise cell proliferation

“…It would be interesting to know whether reduced sensitivity to TCR signaling promotes the expression of Egr2 and GRAIL. Memory CD8 + T cells are susceptible to peripheral tolerance (Kreuwel et al, 2002;Jellison et al, 2012), though memory T cell responses are resistant to co-stimulation blockade and anti-TCR mAb treatment (Miyahara et al, 2012). Defining the role of Egr2, GRAIL, and many other intracellular regulators in memory T cell responses is critical for inducing transplant tolerance and preventing autoimmunity.…”