ABSTRACT
Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)-like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCRα chain usage is widely thought to indicate limited ligand presentation and discrimination within a pattern-like recognition system. Here, we evaluated the TCR repertoire of MAIT cells responsive to three classes of microbes. Substantial diversity and heterogeneity were apparent across the functional MAIT cell repertoire as a whole, especially for TCRß chain sequences. Moreover, different pathogen-specific responses were characterized by distinct TCR usage, both between and within individuals, suggesting that MAIT cell adaptation was a direct consequence of exposure to various exogenous MR1-restricted epitopes. In line with this interpretation, MAIT cell clones with distinct TCRs responded differentially to a riboflavin metabolite. These results suggest that MAIT cells can discriminate between pathogen-derived ligands in a clonotype-dependent manner, providing a basis for adaptive memory via recruitment of specific repertoires shaped by microbial exposure.
Subject(s)
Antigens, Differentiation, B-Lymphocyte/metabolism , Bacteria/immunology , Histocompatibility Antigens Class II/metabolism , Histocompatibility Antigens Class I/metabolism , Mucous Membrane/cytology , Mucous Membrane/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/metabolism , Amino Acid Sequence , Bacteria/drug effects , Cell Line , Clone Cells , Complementarity Determining Regions/chemistry , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor/genetics , Humans , Ligands , Minor Histocompatibility Antigens , Molecular Sequence Data , Mucous Membrane/drug effects , Receptors, Antigen, T-Cell, alpha-beta/genetics , Sequence Homology, Amino Acid , T-Lymphocytes/drug effects , Vitamin B Complex/pharmacologyABSTRACT
BACKGROUND/AIMS: The role of HCV-specific CD4(+) T cells and regulatory T cells in influencing the outcome of antiviral therapy is incompletely defined. METHODS: CD4(+) IFN-gamma ELISPOT assays (n=58) and flow cytometric analysis of FoxP3-expressing T regulatory cells (n=62) were performed on patients from the Virahep-C study at baseline, during and after cessation of antiviral therapy. RESULTS: Total HCV-specific IFN-gamma CD4(+) T cell ELISPOT responses did not increase with therapy, but rather decreased by 8 weeks and remained below baseline 24 weeks after cessation of therapy. There were no statistically significant differences with respect to viral kinetics, race and virologic outcome. In contrast, viral relapse after treatment was associated with a three-fold increase in HCV-specific responses. The frequency and phenotype of regulatory T cells during therapy were not significantly different in terms of race, viral kinetic groups or virologic outcome. CONCLUSIONS: A contraction of HCV-specific CD4(+) T cell responses was found during treatment with recovery of responses in patients experiencing virologic relapse after treatment. The levels of FoxP3-expressing regulatory T cells did not vary by race and were not predictive of virologic outcome. Work is ongoing to explore the contribution of mechanisms independent of CD4(+) T cells in therapy-induced viral clearance.