Gammadelta T cells remain an enigma. They are capable of generating more unique antigen receptors than alphabeta T cells and B cells combined, yet their repertoire of antigen receptors is dominated by specific subsets that recognize a limited number of antigens. A variety of sometimes conflicting effector functions have been ascribed to them, yet their biological function(s) remains unclear. On the basis of studies of gammadelta T cells in infectious and autoimmune diseases, we argue that gammadelta T cells perform different functions according to their tissue distribution, antigen-receptor structure and local microenvironment; we also discuss how and at what stage of the immune response they become activated.

RA is an autoimmune disease characterized by sustained imbalance between pro-and antiinflammatory immune mechanisms. The SOCS proteins are negative regulators of cytokine signaling, but to date there has been little information on their function in disease. The generation of Socs3 -/Dvav mice, which lack SOCS-3 in the hematopoietic and endothelial cell compartment, allowed us to explore the role of endogenous SOCS-3 during acute inflammatory arthritis. Joint inflammation in Socs3 -/Dvav mice was particularly severe and was characterized by increased numbers of neutrophils in the inflamed synovium, bone marrow, peripheral blood, and spleen. These features were most likely due to increased production of and enhanced responsiveness to G-CSF and IL-6 during arthritis in these mice. Local osteoclast generation and bone destruction were also dramatically increased in the absence of SOCS-3, as was macrophage activation. Finally, SOCS-3 was found to negatively regulate CD4 + T lymphocyte activation, including production of the pleiotropic cytokine IL-17. The absence of SOCS-3 therefore had dramatic effects in this disease model, with a broader impact on cellular responses than SOCS-1 deficiency. These findings provide direct in vivo evidence that endogenous SOCS-3 is a critical negative regulator of multiple cell types orchestrating inflammatory joint disease.

Although γδ T cells are involved in the regulation of inflammation after infection, their precise function is not known. Intraperitoneal infection of T cell receptor (TCR)-δ−/− mice with the intracellular bacterium Listeria monocytogenes resulted in the development of necrotic foci in the livers. In contrast, the peritoneal cavities of infected TCR-δ−/− mice contained an accumulation of low density activated macrophages and a reduced percentage of macrophages undergoing apoptosis. γδ T cell hybridomas derived from mice infected with Listeria were preferentially stimulated by low density macrophages from peritoneal exudates of infected mice. Furthermore, primary splenic γδ T cells isolated from Listeria-infected mice were cytotoxic for low density macrophages in vitro, and cytotoxicity was inhibited in the presence of antibodies to the γδ TCR. These results demonstrate a novel interaction between γδ T cells and activated macrophages in which γδ T cells are stimulated by terminally differentiated macrophages to acquire cytotoxic activity and which, in turn, induce macrophage cell death. This interaction suggests that γδ T cells regulate the inflammatory response to infection with intracellular pathogens by eliminating activated macrophages at the termination of the response.

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The aim of our research is to determine the biological function of gamma delta lymphocytes and in particular the role they play in microbial immunity. Although evidence of gamma delta T-cell activation and expansion has been obtained from numerous infectious diseases, how they contribute to pathogen-induced immune responses is still not clear. Based upon extensive studies of gamma delta T-cell involvement in the immune response to viral and bacterial pathogens in both mice and humans, we have uncovered evidence of their direct involvement in terminating host immune responses to infection and preventing chronic disease. We have identified an interaction between peripheral gamma delta T cells and a population of activated, proinflammatory macrophages elicited by infection that occurs late in the course of infection during or after pathogen clearance. As a result of this interaction, activated gamma delta T cells acquire cytotoxic activity and kill the stimulatory macrophages, leading us to propose a model for gamma delta T-cell-macrophage interactions that contributes to macrophage homeostasis, the resolution of inflammatory immune responses, and prevention of chronic inflammatory disease.