Immunoregulation in the tissues by γδ T cells

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Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nature Immunol. 2, 997–1003 (2001).

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Lin, T. et al. Autospecific γδ thymocytes that escape negative selection find sanctuary in the intestine. J. Clin. Invest. 104, 1297–1305 (1999). An interesting paper providing evidence that gut-associated γδ T cells are positively selected in the thymus.

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Smith, A. & Hayday, A. An αβ T-cell-independent immunoprotective response toward gut coccidia is supported by γδ cells. Immunology 101, 325–332 (2000).

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D'Souza, C. D. et al. An anti-inflammatory role for γδ T cells in acquired immunity to Mycobacterium tuberculosis. J. Immunol. 158, 1217–1221 (1997). A good example of how defects in γδ T cells affect the form, but not the overall outcome, of the immune response that develops to a naturally administered pathogen.

Mukasa, A. et al. Bacterial infection of the testis leading to autoaggressive immunity triggers apparently opposed responses of αβ and γδ T cells. J. Immunol. 155, 2047–2056 (1995). A thorough paper showing that the defects in γδ T-cell-deficient mice are evident as overt inflammation, whereas the main consequence of a defect in αβ T cells is failure to control infection.

Mukasa, A., Born, W. & O'Brien, R. L. Inflammation alone evokes the response of a TCR-invariant mouse γδ T-cell subset. J. Immunol. 162, 4910–4913 (1999).

Peng, S., Madaio, M., Hayday, A. C. & Craft, J. Propagation and regulation of systemic autoimmunity by γδ T cells. J. Immunol. 157, 5689–5698 (1996).

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Horner, A. A., Jabara, H., Ramesh, N. & Geha, R. S. γδ T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes. J. Exp. Med. 181, 1239–1244 (1995).

Pao, W. et al. γδ T-cell help for B cells is stimulated by repeated parasitic infection. Curr. Biol. 6, 1317–1325 (1996).

King, D. P. et al. Cutting edge: protective response to pulmonary injury requires γδ T lymphocytes. J. Immunol. 162, 5033–5036 (1999).

Ladel, C. H., Blum, C. & Kaufmann, S. H. E. Control of natural killer cell-mediated innate resistance against the intracellular pathogen Listeria monocytogenes by γδ T lymphocytes. Infect. Immun. 64, 1744–1749 (1996).

Huber, S., Graveline, D., Newell, M., Born, W. & O'Brien, R. Vγ1+ T cells suppress and Vγ4+ T cells promote susceptibility to coxsackievirus B3-induced myocarditis in mice. J. Immunol. 165, 4174–4181 (2000). This study provides evidence that the outcome of immunoregulation by γδ T cells can be complex, with both pro- and anti-inflammatory consequences, depending on which γδ T-cell subsets are dominant.

Huber, S., Sartini, D. & Exley, M. Vγ4+ T cells promote autoimmune CD8+ cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4+ TH1 cells. J. Virol. 76, 10785–10790 (2002).

Hoyne, G. F., Dallman, M. J. & Lamb, J. R. T-cell regulation of peripheral tolerance and immunity: the potential role for Notch signalling. Immunology 100, 281–288 (2000).

Smith, A. L. & Hayday, A. C. Genetic dissection of primary and secondary responses to a widespread natural pathogen of the gut, Eimeria vermiformis. Infect. Immun. 68, 6273–6280 (2000).

Roberts, S. et al. T-cell receptor αβ+ and γδ+ deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc. Natl Acad. Sci. USA 93, 11774–11779 (1996).

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Girardi, M. et al. Resident skin-specific γδ T cells provide local, nonredundant regulation of cutaneous inflammation. J. Exp. Med. 195, 855–867 (2002). This study provides evidence that mice deficient for γδ T cells show a spontaneous loss of regulation of αβ T-cell responses in the skin.

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Poussier, P., Ning, T., Banerjee, D. & Julius, M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 195, 1491–1497 (2002). A clear demonstration that gut-associated unconventional αβ T cells downregulate systemic αβ T-cell-mediated inflammation in the tissues.

Gonzalez, A., Andre-Schmutz, I., Carnaud, C., Mathis, D. & Benoist, C. Damage control rather than unresponsiveness effected by protective Dx5+ T cells in autoimmune diabetes. Nature Immunol. 2, 1117–1125 (2001). An intriguing example of tissue-associated immune regulation of αβ T-cell responses by a subset of αβ T cells expressing a natural killer-cell marker.

Fahrer, A. et al. Attributes of γδ intraepithelial lymphocytes as suggested by their transcriptional profile. Proc. Natl Acad. Sci. USA 98, 10261–10266 (2001).

Shires, J., Theodoridis, E. & Hayday, A. Biological insights into TCRγδ+ and TCRαβ+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).

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Egan, P. & Carding, S. Downmodulation of the inflammatory response to bacterial infection by γδ T cells cytotoxic for activated macrophages. J. Exp. Med. 191, 2145–2158 (2000). A provocative mechanistic explanation for how γδ T cells might suppress the inflammatory response to a bacterial infection.

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Huber, S., Shi, C. & Budd, R. γδ T cells promote a TH1 response during coxsackievirus B3 infection in vivo: role of Fas and Fas ligand. J. Virol. 76, 6487–6494 (2002).

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Wen, L. et al. Primary γδ-cell clones can be defined phenotypically and functionally as TH1/TH2 cells and illustrate the association of CD4 with TH2 differentiation. J. Immunol. 160, 1965–1974 (1998).

Yin, Z. et al. T-bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γ by γδ T cells. J. Immunol. 168, 1566–1571 (2002).

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