Most human peripheral blood gamma delta T lymphocytes respond to hitherto unidentified mycobacterial antigens. Four ligands from Mycobacterium tuberculosis strain H37Rv that stimulated proliferation of a major human gamma delta T cell subset were isolated and partially characterized. One of these ligands, TUBag4, is a 5' triphosphorylated thymidine-containing compound, to which the three other stimulatory molecules are structurally related. These findings support the hypothesis that some gamma delta T cells recognize nonpeptidic ligands.

The recently described staphylococcal enterotoxins (SE) G and I were originally identified in two separate strains of Staphylococcus aureus. We have previously shown that the corresponding genes seg and sei are present in S. aureus in tandem orientation, on a 3.2-kb DNA fragment (Jarraud, J. et al. 1999. J. Clin. Microbiol. 37:2446–2449). Sequence analysis of seg-sei intergenic DNA and flanking regions revealed three enterotoxin-like open reading frames related to seg and sei, designated sek, sel, and sem, and two pseudogenes, ψ ent1 and ψ ent2. RT-PCR analysis showed that all these genes, including seg and sei, belong to an operon, designated the enterotoxin gene cluster (egc). Recombinant SEG, SEI, SEK, SEL, and SEM showed superantigen activity, each with a specific Vβ pattern. Distribution studies of genes encoding superantigens in clinical S. aureus isolates showed that most strains harbored such genes and in particular the enterotoxin gene cluster, whatever the disease they caused. Phylogenetic analysis of enterotoxin genes indicated that they all potentially derived from this cluster, identifying egc as a putative nursery of enterotoxin genes.

Contribution of Vgamma9/Vdelta2 T lymphocytes to immune protection against Mycobacterium tuberculosis is still a matter of debate. It was reported earlier that Vgamma9/Vdelta2 T lymphocytes kill macrophages harboring live M. tuberculosis through a granule-dependent mechanism that results in killing of intracellular bacilli. This study found that Vgamma9/Vdelta2 T lymphocytes reduce the viability of both extracellular and intracellular M. tuberculosis. Granulysin and perforin, both detected in Vgamma9/Vdelta2 T lymphocytes, play a major role, which indicates that Vgamma9/Vdelta2 T lymphocytes directly contribute to a protective host response against M. tuberculosis infection.

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The majority of peripheral blood gamma delta T cells in human adults expresses T cell receptors (TCR) with identical V regions (V gamma 9 and V delta 2). These V gamma 9 V delta 2 T cells recognize the major histocompatibility complex (MHC) class I-deficient B cell line Daudi and broadly distributed nonpeptidic antigens present in bacteria and parasites. Here we show that unlike alpha beta or V gamma 9- gamma delta T cells, the majority of V gamma 9V delta 2 T cells harbor natural killer inhibitory receptors (KIR) (mainly CD94/NKG2A heterodimers), which are known to deliver inhibitory signals upon interaction with MHC class I molecules. Within V gamma 9V delta 2 T cells, KIR were mainly expressed by clones exhibiting a strong lytic activity against Daudi cells. In stark contrast, almost all V gamma 9V delta 2 T cell clones devoid of killing activity were KIR-, thus suggesting a coordinate acquisition of KIR and cytotoxic activity within V gamma 9V delta 2 T cells. In functional terms, KIR inhibited lysis of MHC class I-positive tumor B cell lines by V gamma 9V delta 2 cytotoxic T lymphocytes (CTL) and raised their threshold of activation by microbial antigens presented by MHC class I-positive cells. Furthermore, masking KIR or MHC class I molecules revealed a TCR-dependent recognition by V gamma 9V delta 2 CTL of ligands expressed by activated T lymphocytes, including the effector cells themselves. Taken together, these results suggest a general implication of V gamma 9V delta 2 T cells in immune response regulation and a central role of KIR in the control of self-reactive gamma delta CTL.

SummaryRheumatoid arthritis is a multistep disorder associated with autoimmune features of yet unknown etiology. Implication of viruses such as Epstein-Barr virus (EBV) in rheumatoid arthritis pathogenesis has been suspected on the basis of several indirect observations, but thus far, a direct link between EBV and rheumatoid arthritis has not been provided. Here we show that a large fraction of T cells infiltrating affected joints from a patient with chronic rheumatoid arthritis recognizes two EBV transactivators (BZLF1 and BMLF1) in a major histocompatibility complex-restricted fashion. Responses to these EBV antigens by synovial lymphocytes from several other chronic rheumatoid arthritis panents were readily detectable. Thus these results suggest a direct contribution of EBV to chronic rheumatoid arthritis pathogenesis. They also demonstrate for the first time the occurrence of T cell responses against EBV transactivating factors, which might be central in the control of virus reactivation.

Recent studies demonstrating the existence of murine gamma delta T cell subsets with structurally identical T cell receptors (TcR) suggest that unlike alpha beta T cells, some gamma delta T cells are specialized in the recognition of a limited number of monomorphic antigens. However, this question still remains open in humans, since the TcR structural diversity of their peripheral gamma delta T cells was shown to be extensive. Here we have analyzed in detail the TcR chain genes expressed by human V gamma 9+V delta 2+ peripheral blood lymphocytes (PBL), a major peripheral gamma delta T cell subset in adults and present evidence for an antigen-driven peripheral selection of both TcR gamma and delta junctional motifs among these cells. First, it is shown that the proportion of V gamma 9+V delta 2+ cells expressing the V9JPC1 gamma chain is much higher among PBL than among thymus-derived clones, indicating that preferential use of this J gamma segment is not due to pairing or combinatorial constraints. Second, analysis of V9JPC1 gamma transcripts derived from V gamma 9+V delta 2+ PBL clones revealed a high prevalence of a unique V9JP gamma sequence with limited "N" nucleotide additions and VJ trimming, which could not be accounted for by enzymatic or antigen-independent structural limitations. Third, the TcR delta chain expressed by most V gamma 9+V delta 2+ PBL clones, though diverse in amino acid composition and length, carried a highly distinctive junctional motif, found at a much lower frequency among V2DJ delta sequences derived from V gamma 9-V delta 2+ PBL or V gamma 9+V delta 2+ thymocytes. Together, these results which demonstrate shared gamma and delta junctional features by cells using unique V gamma and V delta genes, suggest that in vivo selection of V gamma 9+V delta 2+ lymphocytes is mediated by a highly restricted number of nominal ligands.

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