RAB11FIP5-Deficient Mice Exhibit Cytokine-Related Transcriptomic Signatures

Rab11 recycling endosomes are involved in immunological synaptic functions, but the roles of Rab11 family–interacting protein 5 (Rab11Fip5), one of the Rab11 effectors, in the immune system remain obscure. Our previous study demonstrated that RAB11FIP5 transcripts are significantly elevated in PBMCs from HIV-1–infected individuals, making broadly HIV-1–neutralizing Abs compared with those without broadly neutralizing Abs; however, the role of Rab11FiP5 in immune functions remains unclear. In this study, a RAB11FIP5 gene knockout (RAB11FIP5(−/−)) mouse model was employed to study the role of Rab11Fip5 in immune responses. RAB11FIP5(−/−) mice exhibited no perturbation in lymphoid tissue cell subsets, and Rab11Fip5 was not required for serum Ab induction following HIV-1 envelope immunization, Ab transcytosis to mucosal sites, or survival after influenza challenge. However, differences were observed in multiple transcripts, including cytokine genes, in lymphocyte subsets from envelope-immunized RAB11FIP5(−/−) versus control mice. These included alterations in several genes in NK cells that mirrored observations in NKs from HIV-infected humans expressing less RAB11FIP5, although Rab11Fip5 was dispensable for NK cell cytolytic activity. Notably, immunized RAB11FIP5(−/−) mice had lower IL4 expression in CD4(+) T follicular helper cells and showed lower TNF expression in CD8(+) T cells. Likewise, TNF-α production by human CD8(+) T cells correlated with PBMC RAB11FIP5 expression. These observations in RAB11FIP5(−/−) mice suggest a role for Rab11Fip5 in regulating cytokine responses.