HLA‐DR4‐restricted T‐cell epitopes from the mycobacterial 60 000 MW heat shock protein (hsp 60) do not map to the sequence homology regions with the human hsp 60

Abstract

SUMMARYThe mycobacterial 60 000 MW heat shock protein (hsp 60) is a major antigen recognized by mycobacteria-reactive human CD4T cells with lymphokine profiles and effector functions consistent with protective immunity. In addition, the presence of a large number of T-cell epitopes presented by several HLA class II molecules makes this antigen relevant to subunit vaccine design. However, the results from animal models as well as human studies suggest that the mycobacterial hsp 60 may induce T-cell-mediated autoimmune conditions. In humans, the expression of HLA-DR4 represents a risk factor for some autoimmune diseases. These observations suggest that the epitopes from the mycobacterial hsp 60 presented to T cells in the context of HLA-DR4 could be relevant to autoimmunity. This is the first report on identification of HLA-DR4-restricted T-cell epitopes from the mycobacterial antigen hsp 60. In total, five epitopes recognized in the context of HLA-DR4 by the M. leprae hsp 60-reactive CD4 T-cell clones from a subject immunized with M. leprae were defined by synthetic peptides. Two of the epitopes were M. leprae-specific (aa 343-355, aa 522-534), whereas three epitopes were common to M. leprae and M. tuberculosis (aa 331-345, aa 441-455, aa 501-515). However, all of these epitopes belong to the regions that are highly divergent between the mycobacterial hsp 60 and the homologous human hsp 60 sequence, suggesting that the T cells recognizing the mycobacterial hsp 60 in the context of HLA-DR4 may not necessarily induce autoreactivity.

Identification and HLA Restriction of Naturally Derived Th1-Cell Epitopes from the SecretedMycobacterium tuberculosisAntigen 85B Recognized by Antigen-Specific Human CD4+T-Cell Lines

“…Recognition of mycobacterial antigens and epitopes by circulating CD4 ϩ T cells is mostly restricted by HLA-DR molecules (26,32,33,39,(43)(44)(45)(46)(47). Consistent with this, inhibition assays with anti-HLA class I and II antibodies showed that only anti-HLA-DR antibody was able to block peptide presentation.…”

“…Inhibition of antigeninduced T-cell proliferation was studied as described previously (26,32,43,45,46) with the monoclonal antibodies W6/32 (anti-HLA class I) and L243 (anti-HLA-DR), purchased from American Type Culture Collection, Rockville, Md., as well as FN81 (anti-HLA-DQ), a gift from S. Funderud, Oslo, Norway. In brief, adherent APC in the wells of 96-well flat-bottom plates were preincubated with the antibodies for 30 min at 37°C in an atmosphere of 5% CO 2 -95% air.…”

Identification of Mycobacterial Recombinant Antigens Recognized by Human T Cells

“…This suggested that 11 T cell clones were specific for M. leprae 65-kD anti gen. The identification of epitopes recognized by M. leprae-and M. tuberculosis-specific T cell clones by using the synthetic peptide ap proach [27][28][29][30][31] may provide the reagents re quired for specific diagnosis of leprosy and tuberculosis. However, the results reported in this study and elsewhere [32] show that a sin gle epitope is not recognized by T cells from all individuals, and therefore, a panel of epi topes will be required for a diagnostic test or for the design of vaccine candidates.…”

Diagnóstico y tratamiento de la lepra

“…No obstante, todos estos epítopos pertenecen a las regiones altamente divergentes entre la HSP 60 micobacteriana y la secuencia homóloga de la HSP 60 humana, lo cual sugiere que los linfocitos que reconocen la HSP 60 micobacteriana en el contexto del HLA-DR4 no necesariamente pueden inducir autoinmunidad. 6 El 69% de pacientes con lepra tuberculoide sin tratamiento son positivos a otro antígeno de 35 kD, y 45% de esos pacientes muestran anticuerpos anti-35 kD. Se observa consistentemente mayor tasa de positividad a los antígenos de 35, 12 y 30 a 40 kD, componentes de M. leprae, en pacientes con lepra lepromatosa que en pacientes con lepra tuberculoide.…”