Influence of HLA-DR on the phenotype of CD4+ T lymphocytes specific for an epitope of the 16-kDa alpha-crystallin antigen of Mycobacterium tuberculosis.
T helper phenotype may be influenced by cytokine milieu, the differential expression of co-stimulatory molecules, antigen dose, and by differences in affinity at the TCR-peptide-MHC interface. We investigated the latter hypothesis by examining the response of six HLA-DR-restricted CD4+ T cell lines specific for the immunodominant and permissively recognized p91-110 epitope of the 16-kDa alpha-crystallin protein of Mycobacterium tuberculosis. Each line was generated from a sensitized HLA-DR-heterozygous donor and all proliferated when peptide was presented by autologous irradiated peripheral blood mononuclear cells. However, when HLA-DR-matched homozygous Epstein-Barr-virus-transformed B cell lines (L-BCL) were used as peptide-presenting cells there was heterogeneity in the response. The most pronounced proliferative response, and the highest IFN-gamma secretion and cytolytic activity was stimulated by L-BCL expressing molecules (DRB1*0101, *1501 and *0401) with high affinity (IC50 < 10 microM) for the 16p91-110 peptide. By comparison, IL-4 secretion or a lower proliferative response could occur when peptide was presented by alleles of high, or of intermediate (10 microM < IC50 < 100 microM), affinity. These data support the hypothesis that the host MHC can influence CD4+ phenotype and have implications for subunit vaccination against tuberculosis.
Agrewala
J N
JN
Tuberculosis and Related Infections Unit, MRC Clinical Sciences Center, Imperial College School of Medicine, Hammersmith Hospital, London, GB.
Wilkinson
R J
RJ
D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000737:chemistry*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000008:administration & dosage / Q000737:chemistry; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010641:Phenotype
D000942:Antigens, Bacterial; D000939:Epitopes; D006684:HLA-DR Antigens; C072681:Mycobacterium tuberculosis antigens; D015847:Interleukin-4; D007371:Interferon-gamma