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Torn between type 1 and type 2 immunity

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Science Immunology  06 Nov 2020:
Vol. 5, Issue 53, eabf4905
DOI: 10.1126/sciimmunol.abf4905

Abstract

DOCK8 uncovers a link between cell integrity and TH2 skewing.

Dedicator of cytokinesis 8 (DOCK8) is an atypical nucleotide exchange factor for CDC42 and has been implicated in various immune responses, including lymphocyte signal transduction, survival, and immune synapse formation. DOCK8 also regulates dendritic cell (DC) and T cell migration in dense tissue environments, and without it, cells undergo migration-induced shattering (termed cytothripsis). DOCK8 deficiency in humans results in immunodeficiency and allergic disease; how DOCK8 deficiency results in biased TH2 skewing has been elusive. Using a Dock8-deficient mouse model, Mandl and colleagues confirmed that loss of DOCK8 leads to TH2-biased CD4+ T cells during multiple type 1 immune responses including infection with Cryptococcus neoformans or influenza A virus and immunization with Complete Freund’s Adjuvant. Using cell-specific Dock8 deletion and adoptive transfer systems, they surprisingly found that the TH2 bias was induced in a T cell extrinsic manner and was likely due to cytothripsis of CX3CR1+ mononuclear phagocytes (MNPs). TH2 skewing was partially driven by enhanced levels of interleukin (IL)-1β in Dock8-deficient mice, possibly derived from the dying MNPs. Moreover, treatment of C. neoformans–infected wild-type mice with apoptotic cells promoted IL-4, -5, and -13 cytokines in CD4+ T cells, revealing that dead cells can provide pro-TH2 skewing signals. Taken together, Schneider et al. revealed how cytothripsis of a potential antigen presenting cell in the lung promotes TH2 cell responses through an unexpected cellular mechanism. Because loss of DOCK8 leads to cytothripsis of multiple cell types, it will be important to define the identity of the CX3CR1+ MNPs and what is unique about this population that regulates type 2 immunity. Although the specific signals from apoptotic cells that favor TH2 responses remain unknown, this study has implications for understanding the general mechanisms of TH2 cell induction.

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