In this issue, Zhang et al. report a novel function for DOCK8 (dedicator of cytokinesis 8) in controlling the structural integrity of lymphocytes. DOCK8 deficiency severely compromised survival of T cells during trafficking through dense tissue networks, impairing skin-specific protective antiviral immune responses.

Identifying the genetic lesions underlying primary immunodeficiencies has an immediate impact on disease diagnosis, therapy, and patient management. It can also provide mechanistic explanations for disease pathogenesis, such as the absence of T and NK cells in X-SCID due to the requirement for γc in IL-7R and IL-15R signaling, and the lack of switched Ig isotypes in hyperimmunoglobulin M syndrome due to the requirement for CD40/CD40L interactions in this process. However, there are other examples where identifying the mutant gene in a particular disease opens up a new field of study, for the simple reasons that little was known about the function of this gene in immune cells. The discovery that biallelic loss-of-function mutations in DOCK8 causes autosomal recessive hyper IgE syndrome falls into this second category. DOCK8 is a guanine nucleotide exchange factor that activates small GTPases such as Cdc42. Previous studies revealed that cytoskeletal defects in DOCK8-deficient B cells, T cells, and NK cells impairs their effector function. However, it is not clear why individuals with DOCK8 mutations specifically develop severe viral infections of the skin. Zhang et al. theorized that since DOCK8-deficient lymphocytes exhibited normal chemotaxis and initial migration into human tissue, these cells may be impaired in their ability to traffic through the dense tissue networks of the skin. By analyzing humans, mice, and cell lines, DOCK8-deficient T and NK cells were found to have aberrant morphologies under conditions that replicated skin infiltration and penetration, and this ultimately contributed to an unusual form of cell death termed “cytothripsis” (cell shattering). This morphological effect was replicated by abolishing expression of Cdc42 or p21-activated kinase (PAK), but not RAC1/2 or the WAS protein, thereby establishing that DOCK8 operates in this setting by activating these regulators of actin polymerization. Overall, the stress experienced by DOCK8-deficient cells moving through dense tissue networks abrogated the generation and maintenance of tissue-resident memory CD8+ T cells that are important for protective immunity at such sites.

This selective inability of effector T cells lacking DOCK8 to efficiently localize to tissues high in collagen content and provide potent antiviral immunity at these sites may explain why DOCK8-deficient patients have heightened susceptibility to skin-trophic viral infections, yet systemic viral infections are more effectively controlled. These findings reveal the morphological flexibility of immune cells that is required for them to execute effector function in nonlymphoid tissues and the critical function of DOCK8/Cdc42/PAK in this process. It will be important to elucidate the mechanism by which DOCK8 integrates into TCR signaling, as well as to assess virus-specific skin-resident memory cells in DOCK8-deficient humans to establish a paucity of these cells at these sites. Identification of the components that regulate lymphocyte integrity, motility, and survival under conditions of migratory stress may provide an opportunity to enhance tissue-specific immunity and memory in patients with germline mutations in this pathway. Eventually, shedding light on the pathology arising in the skin may result in improved outcomes for patients with this often-fatal immunodeficiency.

References

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