Marc Bonneville

Effector functions of γδ T cells influence the outcome of the host responses to infections, injury and malignancy, and they have a role in the pathology of allergic and autoimmune diseases. Although γδ T cells share functional features with other cells of the immune system, specialization of γδ T cell subsets and the timing and tissue localization of their functional engagement makes their responses unique. Effector functions of the γδ T cell subsets develop under the influence of innate programming and environmental signals. Programming during thymocyte maturation restricts the functional potential of populations of γδ T cells expressing given T cell receptors (TCRs) but they retain some degree of functional plasticity that is influenced by the context of an ongoing immune response. The γδ T cells interact with a wide range of cell types, including innate immune cells, T cells and B cells, as well as non-immune tissue cells. Such interactions might trigger regulatory and cytotoxic responses of γδ T cells, they also induce innate and adaptive immunity, and they can promote tissue repair and wound healing. Although studies in mice have been useful in identifying possible roles for γδ T cells in vivo, several differences between mouse and human subsets limit the translation of these findings to human γδ T cells. Nevertheless, comparison of functionally analogous subsets in both species is expected to provide insight into the immunobiology of human γδ T cells. Clinical-grade compounds that mediate human γδ T cell activation have been shown to accelerate pathogen clearance and tissue repair in bacterial and viral infections, and such treatments correlate with disease stabilization or tumour regression in patients with malignancies. A key remaining challenge for future study is the γδ TCR itself, of which the precise mode of action and role in the development and triggering of γδ T cell effector functions remains poorly understood.

The T-cell response to human cytomegalovirus is characterized by a dramatic reduction of clonal diversity in patients undergoing chronic inflammation or immunodepression. In order to check whether all the selected high-avidity T-cell clones recognize the immunodominant pp65 peptide antigen pp65_495-503 (NLVP­MVATV) presented by the major histocompatibility complex (MHC) molecule HLA-A2 in a similar manner, several public high-affinity T-cell receptors (TCRs) specific for the pp65_495-503-HLA-A2 complex have been investigated. Expression, purification and crystallization were performed and preliminary crystallographic data were collected to 4.7 Å resolution for the RA15 TCR in complex with the pp65_495-503-HLA-A2 complex. Comparison of the RA15-pp65_495-503-HLA-A2 complex molecular-replacement solution with the structure of another high-affinity pp65_495-503-HLA-A2-specific TCR, RA14, shows a shared docking mode, indicating that the clonal focusing could be accompanied by the selection of a most favoured peptide-readout mode. However, the position of the RA15 V domain is significantly shifted, suggesting a different interatomic interaction network.

Both strong antigenic avidity and acquisition of proper effector functions contribute to the efficacy of antiviral T cell responses. To correlate these parameters with the outcome of hepatitis C virus (HCV) infection, we characterized HCV-specific CD8 T cell lines isolated after immunomagnetic sorting of peripheral blood mononuclear cells from human leukocyte antigen A*02 (HLA-A*02) individuals with various HCV serological statuses, using recombinant HLA-A*0201 multimers loaded with three immunodominant HCV genotype 1-derived epitopes. CD8 T cells specific for these three epitopes were derived from most HLA-A*0201 individuals, regardless of their HCV serology or clinical outcome. Donors recovered from genotype 1 HCV infection were enriched for high-avidity T cells with enhanced interferon gamma (IFN-γ), tumor necrosis factor alpha, and cytotoxic T lymphocyte responses, when compared with seronegative donors and seropositive patients infected with irrelevant HCV genotypes. Patients chronically infected with genotype 1 strain yielded almost exclusively low-avidity T cells, whose hyporesponsiveness was primarily attributable to low T cell receptor (TCR) avidity rather than intrinsic functional defects. Conclusion: This study suggests that strong IFN-γ responses associated with efficient viral clearance primarily result from Ag-driven selection/survival of HCV-specific T cells expressing high-avidity TCR. It also suggests a link between the quality of the initial HCV-specific T cell repertoire and susceptibility to chronic infection. (Hepatology 2008.)

Summary:  Although γδ T cells express clonally distributed T‐cell receptors (TCRs), a hallmark of adaptive immunity, they are classically considered as innate‐like effectors, owing to the high frequency of preactivated γδ T cells, with restricted antigen recognition repertoire in particular tissue locations. Actually, such features are shared only by a fraction of γδ T‐cell subsets located in the skin and reproductive organ mucosa in rodents or in peripheral blood in humans. By contrast, other γδ subsets, e.g. those found in rodent and human spleen, show diverse antigenic reactivity patterns and mixed naive/memory phenotypes. Thus, γδ T cells are made of both ‘primitive’ subsets endowed with innate‐like properties and ‘evolved’ subsets able to mount anamnestic responses like conventional major histocompatibility complex‐restricted αβ T cells. In this article, we show that human γδ T cells, although heterogeneous, do share recurrent innate features that distinguish them from mainstream αβ T cells. In particular, most of them are activated on TCR‐ or natural killer receptor‐mediated recognition of a restricted set of conserved yet poorly defined endogenous stress determinants. This rather simple recognition mechanism allows human γδ T cells to discriminate healthy cells from altered cells and to exert a variety of immunostimulatory or regulatory functions. The recent availability of synthetic γδ T‐cell agonists mimicking these natural stress‐induced ligands have fostered development of immunotherapeutic strategies, with broad indications against infectious and tumor diseases, which are briefly reviewed here.

The antigenic repertoire of T cells has long been considered as exclusively composed of proteins and peptides. This view has been recently challenged by the discovery of CD1 molecules, a set of weakly polymorphic MHC class I-related receptors able to present lipid antigens to T cells. An updated picture of the biology of human CD1-restricted T cells is provided here, which highlights the unique features of these lymphoid effectors and the way they synergize with other innate and adaptive immune players to ensure protective immunity against tumors and pathogens.

MHC class I-specific inhibitory receptors are expressed by a subset of memory-phenotype CD8⁺ T cells. Similar to NK cells, MHC class I-specific inhibitory receptors might subserve on T cells an important negative control that participates to the prevention of autologous damage. We analyzed here human CD8⁺ T cells that express the Ig-like MHC class I-specific inhibitory receptors: killer cell Ig-like receptor (KIR) and CD85j. The cell surface expression of Ig-like inhibitory MHC class I receptors was found to correlate with an advanced stage of CD8⁺ T cell maturation as evidenced by the reduced proliferative potential of KIR⁺ and CD85j⁺ T cells associated with their high intracytoplasmic perforin content. This concomitant regulation might represent a safety mechanism to control potentially harmful cytolytic CD8⁺ T cells, by raising their activation threshold. Yet, KIR⁺ and CD85j⁺ T cells present distinct features. KIR⁺CD8⁺ T cells are poor IFN-γ producers upon TCR engagement. In addition, KIR are barely detectable at the surface of virus-specific T cells during the course of CMV or HIV-1 infection. By contrast, CD85j⁺CD8⁺ T cells produce IFN-γ upon TCR triggering, and represent a large fraction of virus-specific T cells. Thus, the cell surface expression of Ig-like inhibitory MHC class I receptors is associated with T cell engagement into various stages of the cytolytic differentiation pathway, and the cell surface expression of CD85j or KIR witnesses to the history of qualitatively and/or quantitatively distinct T cell activation events.