DOCK8 is essential for T‐cell survival and the maintenance of CD8⁺ T‐cell memory

Abstract

Deficiency in the guanine nucleotide exchange factor DOCK8 causes a human immunodeficiency syndrome associated with recurrent sinopulmonary and viral infections. We have recently identified a DOCK8-deficient mouse strain, carrying an ethylnitrosourea-induced splice-site mutation that shows a failure to mature a humoral immune response due to the loss of germinal centre B cells. In this study we turned to T-cell immunity to investigate further the human immunodeficiency syndrome and its association with decreased peripheral CD4+ and CD8+ T cells. Characterisation of the DOCK8-deficient mouse revealed T-cell lymphopenia, with increased T-cell turnover and decreased survival. Egress of mature CD4+ thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two-fold reduction in peripheral naïve T cells, the DOCK8-deficient mice generated a normal primary CD8+ immune response and were able to survive acute influenza virus infection. The limiting effect of DOCK8 was in the normal survival of CD8+ memory T cells after infection. These findings help to explain why DOCK8-deficient patients are susceptible to recurrent infections and provide new insights into how T-cell memory is sustained.

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…These mice, designated Dock8 -/-mice, express no detectable DOCK8 protein (16). As previously reported (15,28), the percentage and number of CD4 + T cells and marginal zone B cells in the spleens of Dock8 -/-mice were decreased compared with WT controls (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.94298DS1). Proliferation and IL-2 production and secretion by CD4 +…”

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

“…The majority of these patients have low numbers of CD4 + and CD8 + T cells in the blood. DOCK8 has been shown to regulate B, T, NKT, and NK cells and DCs functions in mice (17,(20)(21)(22)(23)(24)(25)(26). We have recently uncovered a poten-…”

DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

“…Although T-cell development occurred normally in the absence of DOCK8 (supplemental Figure 2), the numbers of CD4 ϩ and CD8 ϩ T cells in the spleen and the peripheral LNs were reduced to 50%-60% of the Dock8 ϩ/Ϫ levels ( Figure 1A-B), as reported in the N-ethyl-N-nitrosourea-induced mutant mice. [19][20][21] This reduction did not result from the defect in T-cell homing, because Dock8 ϩ/Ϫ and Dock8 Ϫ/Ϫ T cells migrated comparably into the T-cell zone of secondary lymphoid organs when IV injected into C57BL/6 mice ( Figure 1C). Dock8 Ϫ/Ϫ mice also exhibited a significant reduction of marginal zone B (MZB) cells ( Figure 1D).…”