The heme moiety of cytochrome c is an autoreactive Ir gene-restricted T cell epitope.

Abstract

The phenomenon ofTh receptor recognition of protein antigens has been intensively studied during recent years, leading to a more comprehensive understanding of the physical and chemical requirements that determine the mode of interaction between antigen, the MHC-restricting element (class II gene products), and the TCR complex (1-4). The current working hypothesis to explain the process of antigen presentation states that the protein antigen must be proteolytically digested (4-6) or at least denatured (7) inside acidic compartments (probably endosomes) within the APC (e.g., B cells, macrophages, dendritic cells) (8-10) . The pathways of antigen degradation and subsequent emergence ofthe immunogenic peptide onto the plasma membrane of the presenting cell in conjunction with the appropriate class II (Ia) heterodimer are still unknown, although it appears most likely that the peptide forms a stable complex with the Ia molecule before the TCR recognition event (I1-13). Recent data emerging from several laboratories (14, 15) have provided strong evidence that there exists only a single site on the class II heterodimer that can interact directly with the immunogenic peptide. In the case ofthe murine system, any given individual may express a limited number of Ia molecules, thus, the peptide-binding site on the class II heterodimer must be of extremely broad specificity in order to accept the large variety of antigenic peptides likely to be encountered.The learning of MHC restriction is acquired in the thymus where immature thymocytes are selected on the basis of their ability to recognize antigen in the context of self-MHC (16,17). It is at this stage that tolerance to self antigen is acquired; at least in the case of antigens present in the thymic environment (18)(19)(20). However, tolerance to antigens never expressed in the thymus must be established after the mature T cell has arrived in the periphery. Despite evidence that a deletion event for self-reactive T cell clones is operative in the thymus (20), there have been many examples where the existence of self-reactive T cell clones has been demonstrated to both self-MHC antigens (21, 22) and non-MHC self antigens (23,24). Thus, in these instances, it appears that clonal deletion is not effective. Active regulatory systems, involving suppressor T cells, have been proposed to account for the suppression of such self-reactive T cell clones under normal circumstances (25,26).

An Analysis of the Structure and Antigenicity of Different Forms of Human Thyroid Peroxidase

“…Other components of TPO, such as the heme group, may contribute to the antigenicity of the enzyme. Support for this comes from the recent finding that the heme group of cytochrome c is part of a T cell epitope (26). It would seem possible, however, that there are autoantibody epitopes in TPO that would require a dimer of two TPO polypeptide chains.…”

Regulatory T cells essential to prevent the loss of self-tolerance in murine models of erythrocyte-specific autoantibody responses

“…An intriguing possibility for this is the very strong stimulation of CD4 ? T-cell (from all strains of mice) proliferation and cytokine production by hemoglobin or heme [69,[72][73][74], which is likely to be engulfed, processed, and presented with Band 3 or glycophorins in APC [66].…”

Rational approaches to immune regulation

“…In other studies on the immune response to self-antigens, we are examining an unusual autoantigenic T cell response to the heme moiety of hemoproteins that we discovered some years ago (77). This nonprotein, selfantigen is the prosthetic group of a number of hemoproteins, which are ubiquitous in most tissues, including the thymus.…”

“…This nonprotein, selfantigen is the prosthetic group of a number of hemoproteins, which are ubiquitous in most tissues, including the thymus. Therefore, it was of considerable interest to note that T cells freshly explanted from naive mice raised a potent proliferative response to heine in primary MLR, suggesting that heme reactive T cells occur at high frequency in the periphery (77).…”

“…T cells from mice of the H-2 s haplotype (SJL, B10.S, and A.SW) exhibit a high responder phenotype when stimulated by heme in bulk primary assays, whereas mice of the H-2 d haplo- 200 Paterson type (B10.D2 and BALB/c) are low responders (77). Using limiting dilution analysis we found that the potent primary proliferative responses by Tcells from H-2 s mice reflect a high frequency (0.26-0.45%) of heme-responsive T cells in the periphery (78).…”