T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4+T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca2+levels and regulated via N-Wasp and NIK. Specific interference with TCR-induced formation of nuclear actin filaments impairs production of effector cytokines and prevents generation of antigen-specific antibodies but does not interfere with immune synapse formation and cell proliferation. Ca2+-regulated actin polymerization in the nucleus allows CD4+T cells the rapid conversion of TCR signals into effector functions required for T cell help.
Failures to produce neutralizing antibodies upon HIV‐1 infection result in part from B‐cell dysfunction due to unspecific B‐cell activation. How HIV‐1 affects antigen‐specific B‐cell functions remains elusive. Using an adoptive transfer mouse model and ex vivo HIV infection of human tonsil tissue, we found that expression of the HIV‐1 pathogenesis factor NEF in CD4 T cells undermines their helper function and impairs cognate B‐cell functions including mounting of efficient specific IgG responses. NEF interfered with T cell help via a specific protein interaction motif that prevents polarized cytokine secretion at the T‐cell–B‐cell immune synapse. This interference reduced B‐cell activation and proliferation and thus disrupted germinal center formation and affinity maturation. These results identify NEF as a key component for HIV‐mediated dysfunction of antigen‐specific B cells. Therapeutic targeting of the identified molecular surface in NEF will facilitate host control of HIV infection.
This work was supported by Deutsche Forschungsgemeinschaft Grants FA378/10-2 and SFB1129 (to O.T.F.) and SFB1129 (to M.T.), and the Nakatani Foundation (to M.T.). N. Tsopoulidis was supported by a Heidelberg Biosciences International Graduate School fellowship. O.T.F. and M.T. are members of the CellNetworks Cluster of Excellence (EXO81). O.T.F. designed the study, interpreted results, and wrote the manuscript together with B.S. M.L.-M. conducted and analyzed the experiments shown in Figs. 1-3 and 5. S.K. conducted and analyzed the in vivo homing experiments. B.S. carried out the transendothelial migration experiments together with R.L., conducted the Seahorse analyses with help from J.W. and G.C., and analyzed the data. N. Tsopoulidis recorded the movies analyzed in Figs. 4 and 5. J.T. and M.T. generated and interpreted the power spectrum analyses (Fig. 4B-G).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.