T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naïve T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.

T lymphocytes respond to foreign antigens both by producing protein effector molecules known as lymphokines and by multiplying. Complete activation requires two signaling events, one through the antigen-specific receptor and one through the receptor for a costimulatory molecule. In the absence of the latter signal, the T cell makes only a partial response and, more importantly, enters an unresponsive state known as clonal anergy in which the T cell is incapable of producing its own growth hormone, interleukin-2, on restimulation. Our current understanding at the molecular level of this modulatory process and its relevance to T cell tolerance are reviewed.

No abstract

No abstract

Despite a large body of evidence concerning the phenomenon of immune tolerance at the T cell level, the actual mechanism of unresponsiveness is not understood . Experimentally, T cell unresponsiveness can be induced in adults by the intravenous injection of high doses of soluble antigen (1) or of antigen coupled to syngeneic splenocytes (reviewed in references 2-6) . Two major hypotheses have been proposed (3-6) to explain unresponsiveness : regulation by suppressor T cells or direct inactivation of responding T cells by antigen.The suppression model of unresponsiveness states that a complex circuit of interacting suppressor T cells prevent the expression of inducer T cell function. The antigen and MHC specificity of suppression has been shown in most systems to be different from that of inducer T cells, e. g., inducer T cells recognize antigen in association with class 11 MHC (Ia) molecules, while suppressor T cells often recognize antigen in an unrestricted fashion, or in association with 1-J molecules (2,7,8). However, several instances of la-restricted antigen recognition by suppressor T cells have been described (9, 10). As an alternative to suppression, models of direct T cell inactivation (clonal deletion) state that under certain conditions inducer T cells of the appropriate specificity are functionally or physically deleted after interaction with antigen and la molecules (3-6).Attempts to distinguish between suppression and clonal deletion models have been greatly hampered by the lack of in vitro model systems with which to study the inductive events leading to unresponsiveness . Lamb and coworkers (11) have reported that class I1-restricted human T cell clones could be rendered unresponsive in vitro after incubation with free antigen. Although this result suggested that tolerance induction and T cell activation had different specificities, subsequent studies by these investigators (12) showed that unresponsiveness induced in vitro could be blocked by anti-class 11 antibodies . The relationship of these in vitro observations to the in vivo phenomenon of T cell tolerance induction remained unclear,To address these issues, we examined the specificity of tolerance induction both in vivo and in vitro using the well-defined response of B 10 .A mice to pigeon cytochrome c as a model system . Previous studies (13) have shown that splenocytes coupled with peptide antigens via the chemical crosslinker I-ethyl-3-(3-dimethyl-M. K. Jenkins is a recipient of an Arthritis Foundation postdoctoral fellowship .

T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. Using microarray analysis we have identified here early growth response gene 2 (Egr-2) and Egr-3 as key negative regulators of T cell activation. Overexpression of Egr2 and Egr3 was associated with an increase in the E3 ubiquitin ligase Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr3(-/-) mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance. These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program.

To complete their maturation, most immature thymocytes depend on the simultaneous engagement of their antigen receptor [alpha beta T cell receptor (TCR)] and their CD4 or CD8 coreceptors with major histocompatibility complex class II or I ligands, respectively. However, a normal subset of mature alpha beta TCR+ thymocytes did not follow these rules. These thymocytes expressed NK1.1 and a restricted set of alpha beta TCRs that are intrinsically class I-reactive because their positive selection was class I-dependent but CD8-independent. These cells were CD4+ and CD4-8- but never CD8+, because the presence of CD8 caused negative selection. Thus, neither CD4 nor CD8 contributes signals that direct their maturation into the CD4+ and CD4-8- lineages.

A role for DNA demethylation in transcriptional regulation of genes expressed in differentiated somatic cells remains controversial. Here, we define a small region in the promoter-enhancer of the interleukin-2 (Il2) gene that demethylates in T lymphocytes following activation, and remains demethylated thereafter. This epigenetic change was necessary and sufficient to enhance transcription in reporter plasmids. The demethylation process started as early as 20 minutes after stimulation and was not prevented by a G1 to S phase cell cycle inhibitor that blocks DNA replication. These results imply that this demethylation process proceeds by an active enzymatic mechanism.