Macrophage migration inhibitory factor regulates innate γδ T-cell responses via IL-17 expression

T cells expressing invariant gamma delta antigen receptors (gamma delta T cells) bridge innate and adaptive immunity and facilitate barrier responses to pathogens. Macrophage migration inhibitory factor (MIF) is an upstream mediator of host defense that up-regulates the expression of pattern recognition receptors and sustains inflammatory responses by inhibiting activation-induced apoptosis in monocytes and macrophages. Surprisingly, Mif(-/-) gamma delta T cells, when compared with wild type, were observed to produce >10-fold higher levels of the proinflammatory cytokine IL-17 after stimulation with gram-positive exotoxins. High-IL-17 expression was associated with the characteristic features of IL-17-producing gamma delta T (gamma delta 17) cells, including expression of IL-23R, IL-1R1, and the transcription factors ROR gamma t and Sox13. In the gram-positive model of shock mediated by toxic shock syndrome toxin (TSST-1), Mif(-/-) mice succumbed to death more quickly with increased pulmonary neutrophil accumulation and higher production of cytokines, including IL-1 beta and IL-23. Mif(-/-) gamma delta T cells also produced high levels of IL-17 in response to Mycobacterium lipomannan, and depletion of gamma delta T cells improved survival from acutely lethal Mycobacterium infection or TSST-1 administration. These data indicate that MIF deficiency is associated with a compensatory amplification of gamma delta 17 cell responses, with implications for innate immunity and IL-17-mediated pathology in situations such as gram-positive toxic shock or Mycobacterium infection.-Kim, H. K., Garcia, A. B., Siu, E., Tilstam, P., Das, R., Roberts, S., Leng, L., Bucala, R. Macrophage migration inhibitory factor regulates innate gamma delta T-cell responses via IL-17 expression.