Other Hypotheses

It is possible that the immune preference for chaperonins is due to exposure early in life to environmental bacteria that share epitopes with mycobacterial chaperonins. It is difficult to see how this can be true, because there is a high frequency of responses to mycobacterial cpn60 in the cord blood of newborn infants who have not been exposed to environmental bacteria. Another possibility is that bacteria synthesize large amounts of chaperonins, particularly when they are stressed, and this accounts for the dominance of chaperonins over other antigens. Although it is well known that stressed bacteria synthesize chaperonins in culture, the relative proportions of bacterial chaperonin versus other proteins produced during infection, for example, in active tuberculosis, still requires further investigation.

a. 78 Cells. T lymphocytes bear the T cell antigen receptor (TCR; see Fig. 1). The majority of T cells recognize antigen through TCR which consists of two chains called a and (3. These cells require peptide fragments to be presented to them bound to the MHC, which resides on the surface of antigen-presenting cells such as macrophages. A further, smaller subset of T cells (1.5% of the total T cell population) recognizes antigen via a TCR that has y and 8 chains (Brenner et al., 1988). Interestingly, 10-20% of yd T cells in the adult mouse react to cpn60 (O'Brien et al., 1992) and to the 17 amino acid synthetic peptide corresponding to amino acids 180-196 of the M. leprae cpn60 sequence. A synthetic peptide representing the equivalent region of murine cpn60 also induces responses of 78 T cell hybridomas, although most react weakly when compared to responses to the mycobacterial peptide (Born et al., 1990). Furthermore, human peripheral 78 T cells recognize cpn60 on the surface of human cells, and this recognition can be blocked by a monoclonal antibody against cpn60 (Kaur et al., 1993). Do changes in the expression of self-cpn60 act as a signal for the detection and elimination of abnormal cells such as those that are infected or malignant (Young and Elliott, 1989)? Although self-cpn60-related protein is constitutively expressed on the surface of human cells (Jarjour et al., 1990), interferon--/ stimulates the expression of a surface-localized form of cpn60 on murine bone marrow macrophages (Kaufmann et al., 1990). In areas of inflammation, such as multiple sclerosis brain lesions, there is colocalization of y8 T cells and cpn60-expressing oligodendrocytes (Selmaj et al., 1991). In addition, heat shock proteins and heat shock can regulate the expression of the murine class lb molecules that may be the antigen-presenting molecules for yS T cells (Imani and Soloski, 1991). This evidence supports the idea that chaperonins are upregulated in stressful situations such as inflammation. The possibility that yS T cells eliminate cpn60-expressing cells is supported by the finding that cpn60-related surface protein is recognized by T cell clones that specifically lyse cpn60-expressing Daudi cells (Fisch et al., 1990).

However, the role of y8 T cells remains controversial. Despite the use of monoclonal antibodies that are highly specific for mammalian cpn60 (Kaufmann, 1994) and that immunoprecipitate surface molecules of the expected size, extensive microsequencing of these proteins is required to be certain that they are expressed as the full-length polypeptides. Further issues that need attention are the regulation of cpn60 expression in intact animals and whether it is the self or the microbial peptide that is recognized. On a wider front, the relative importance of chaperonins in relation to other molecules such as protease-resistant ligands, which also stimulate yS T cells (Pfeffer et al., 1990), needs further study. Finally, there is the question of the mechanism of action of the cpn60 peptide that stimulates yS T cells. It is tempting to compare its action with that of superantigen on a/3 cells, but there are several differences between superantigen and cpn60. For instance, a/8 superantigen responses require MHC class II-presenting cells, whereas the cpn60 peptide does not require class II molecules for its action on y§ T cells. It is also a short peptide of cpn60 that is active, whereas superantigen needs to be in its native, globular form. In addition, the cpn60 peptide requires Vy and VS chains, but superantigen does not operate by binding to these chains.

b. aP T Lymphocytes. This type of lymphocyte forms the majority of the T lymphocyte population. These lymphocytes recognize antigens bound to MHC on the surface of antigen-presenting cells (see Fig. 1).

There are two types of a/3 T cell, the helper T cell and the cytotoxic T lymphocyte. Helper T cell stimulation by antigen bound to class IIMHC leads to activation of B lymphocytes to produce antibody, and priming of macrophages for microbicidal action. Cytotoxic T cells lyse cells that present antigen usually bound to class I MHC. Cytotoxic T cells are involved in the elimination of malignant or infected cells.

In animals that have been immunized with Mycobacterium spp. both cpn60 (Kaufmann et ai, 1987; Lamb et ai, 1988) and cpnlO (Minden et al., 1984) are recognized by a/3 T cells. Healthy humans and patients with mycobacterial disease also react to cpn60 (Ilangumaran et ai, 1994; Emmrich et ai, 1986; Oftung et ai, 1987; Adams et ai, 1990) and to cpnlO (Mehra et ai, 1992) with antigen-specific helper and cytotoxic T cell responses. In the author's laboratory, healthy human peripheral blood mononuclear cells are found to respond, quite weakly, to M. tuberculosis cpnlO peptides (Fig. 2). These responses are MHC restricted (data not shown). This and previous work, cited above, suggest that there are low numbers of antichaperonin-specific lymphocytes circulating in the blood, even in healthy people.

Do human T cells recognize human chaperonins? The answer is unequivocally affirmative (reviewed in Kaufmann, 1994). For example, T cells can react with epitopes of chaperonin that are shared between self and non-self. Importantly, anti-self-chaperonin-specific responses occur in healthy adult individuals, as well as those with disease. This observation means that self-chaperonin-reactive T cells are not deleted in the thymus but are a normal component of the immune system. This rather uncomfortable idea raises the question of the function of these cells. Are they poised to defend the body against microbial invaders? There is some evidence to suggest that they are, and this evidence is discussed in Section III,A). Do they have an immune self-surveillance role whereby they recognize and lyse stressed host cells, for example, cells that are infected, malignant, or senescent? There is evidence to support the concept of immune surveillance. Murine cytotoxic T cells specific for M. tuberculosis cpn60 lyse stressed murine macrophages. Stress may be induced by interferon treatment or infection with cytomegalovirus (Koga et al., 1989). Antisense oligonucleotide treatment of stressed macrophages interferes with chaperonin synthesis and prevents lysis by the chaperonin-specific T cells (Steinhoff et al., 1994). These data show that host cpn60 is processed in stressed cells and that cpn60 epitopes are presented to T cells bound to MHC class I. Furthermore, the amino acid

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