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Continuous exposure of tissue antigen (Ag) to the autoantigen-specific regulatory T cells (Treg) is required to maintain Treg-dependent systemic tolerance. Thus, testis autoantigens, previously considered as sequestered, may not be protected by systemic tolerance. We now document that the complete testis antigen sequestration is not valid. The haploid sperm Ag lactate dehydrogenase 3 (LDH3) is continuously exposed and not sequestered. It enters the residual body (RB) to egress from the seminiferous tubules and interact with circulating antibody (Ab). Some LDH3 also remains inside the sperm cytoplasmic droplets (CD). Treg-depletion in the DEREG mice that express diphtheria toxin receptor on the Foxp3 promoter results in spontaneous experimental autoimmune orchitis (EAO) and Ab to LDH3. Unlike the wild-type male mice, mice deficient in LDH3 (wild-type female or LDH3NULLmales) respond vigorously to LDH3 immunization. However, partial Treg depletion elevated the wild-type male LDH3 responses to the level of normal females. In contrast to LDH3, zonadhesin (ZAN) in the sperm acrosome displays properties of a sequestered Ag. However, when ZAN and other sperm Ag are exposed by vasectomy, they rapidly induce testis Ag-specific tolerance, which is terminated by partial Treg-depletion, leading to bilateral EAO and ZAN Ab response. We conclude that some testis/sperm Ag are normally exposed because of the unique testicular anatomy and physiology. The exposed Ag: 1) maintain normal Treg-dependent systemic tolerance, and 2) are pathogenic and serve as target Ag to initiate EAO. Unexpectedly, the sequestered Ags, normally non-tolerogenic, can orchestratede novoTreg-dependent, systemic tolerance when exposed in vasectomy.

Previously we have shown that T cell responses to the mycobacterial 60-kDa heat shock protein (hsp60) peptide M256–270 mediated protection against adjuvant arthritis in Lewis rats. We have demonstrated now that M256–270-primed T cells become highly reactive to naive syngeneic APC upon repetitive restimulation in vitro with peptide M256–265, comprising the conserved core of peptide M256–270. These autoproliferative responses in the absence of added Ag were MHC class II restricted and resulted in the production of IL-4/IL-10 and IFN-γ. Enhanced autoproliferation and expression of the cell surface molecule B7.2 by these T cells were observed in response to syngeneic heat-shocked APC, which indicated that the autoproliferation and expression of B7.2 resulted from the recognition of endogenously expressed and processed hsp. Despite their strong autoreactivity, upon transfer such T cells were found to induce a significant disease reduction in adjuvant arthritis. In contrast, T cells both primed and restimulated with peptide M256–270 became unresponsive toward syngeneic APC as well as toward the conserved core peptide M256–265, and they were devoid of protective capacity. This study demonstrates that the loss of self-tolerance toward hsp60 does not necessarily lead to autoimmune disease, but that hsp60-specific self-reactive and autoproliferative T cells may mediate T cell regulation in arthritis.

Heat shock proteins (Hsps) are remarkably immunogenic, despite their high degree of evolutionary conservation. Experimental and clinical observations on autoimmune diseases indicate that immune responses to Hsps arise spontaneously during the disease process. Based on current evidence, Willem van Eden and colleagues argue that such immunity to Hsps is part of a normal immunoregulatory T-cell response with disease controlling potential.

We previously reported that resistance to the induction of adjuvant arthritis after preimmunization with mycobacterial hsp60 was mediated by T cells recognizing a conserved epitope (M256-270) of mycobacterial hsp60. These T cells were cross-reactive with the homologous rat hsp60 peptide sequence and the natural self-epitope on stressed antigen-presenting cells. Recognition of peptide M256-265, the conserved core of peptide M256-270, was shown to be essential for the generation of self-reactive T cells. The rat homologue of peptide M256-265, peptide R256-265, differs with three conservative amino acid substitutions from the mycobacterial core peptide. Thus peptide R256-265 could act as an altered peptide ligand with the potential of inducing a different functional phenotype in M256-270-specific T cells. We now show that peptide R256-265 was recognized by M256-270-specific T cells as a partial agonist, inducing TCR down-regulation and up-regulation of activation/adhesion molecules in the absence of proliferative responses. Peptide R256-265 did not induce anergy but induced B7-2 (but not B7-1) expression on M256-270-specific T cells, as opposed to the mycobacterial peptide, which preferentially induced B7-1. These effects were more pronounced at low peptide concentrations. Therefore also in vivo at the more relevant low physiological level of expression, the self-hsp could induce such phenotype. It is discussed how this selective up-regulation of B7-2 expression on (self-hsp60) autoreactive T cells might be a way by which destructive autoimmune responses are controlled.