The Inhibitory Receptor BTLA Controls γδ T Cell Homeostasis and Inflammatory Responses

• Published in: Immunity (Cambridge, Mass.) Mass.), 2013-12, Vol.39 (6), p.1082-1094
• Main Authors: Bekiaris, Vasileios, Šedý, John R., Macauley, Matthew G., Rhode-Kurnow, Antje, Ware, Carl F.
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Disease Models, Animal; Flow Cytometry; Gene Deletion; Homeostasis; Humans; Inflammation; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.10.017

γδ T cells rapidly secrete inflammatory cytokines at barrier sites that aid in protection from pathogens, but mechanisms limiting inflammatory damage remain unclear. We found that retinoid-related orphan receptor gamma-t (RORγt) and interleukin-7 (IL-7) influence γδ T cell homeostasis and function by regulating expression of the inhibitory receptor, B and T lymphocyte attenuator (BTLA). The transcription factor RORγt, via its activating function-2 domain, repressed Btla transcription, whereas IL-7 increased BTLA levels on the cell surface. BTLA expression limited γδ T cell numbers and sustained normal γδ T cell subset frequencies by restricting IL-7 responsiveness and expansion of the CD27−RORγt+ population. BTLA also negatively regulated IL-17 and TNF production in CD27− γδ T cells. Consequently, BTLA-deficient mice exhibit enhanced disease in a γδ T cell-dependent model of dermatitis, whereas BTLA agonism reduced inflammation. Therefore, by coordinating expression of BTLA, RORγt and IL-7 balance suppressive and activation stimuli to regulate γδ T cell homeostasis and inflammatory responses. [Display omitted] •IL-7 induces BTLA expression and RORγt represses BTLA transcription•BTLA restricts γδ T cell expansion during homeostasis and inflammation•BTLA regulates γδ T cell production of IL-17 and TNF•BTLA-deficient animals are susceptible to γδ T cell-dependent dermatitis