AUTHOR=O’Brien Sarah A. , Zhu Minghua , Zhang Weiguo 

TITLE=Spontaneous Differentiation of T Follicular Helper Cells in LATY136F Mutant Mice

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.656817

DOI=10.3389/fimmu.2021.656817

ISSN=1664-3224

ABSTRACT=Mice with a mutation at the LAT PLCγ1 binding site (Y136) have a defect in thymocyte development due to dampened TCR signaling. CD4+ T cells that do reach the periphery are hyper-activated and skewed to Th2. Over time, these mice develop an autoimmune-like syndrome, characterize by T cell infiltration into various organs, and B cell activation, isotype switching, and autoantibody production. In this study, we examined IL4 production by CD4+ T cells using the KN2 reporter mice, in which huCD2 expression marks T cells that are actively producing IL4 protein. We demonstrated that despite the fact that the majority of CD4+ T cells were skewed to Th2 and were GATA3+, only a small subset of the LATY136F T cells were actively secreting IL4. These T cells were Tfh cells that expressed BCL6 and were localized to B cell-rich germinal centers within the spleen. Interestingly, these Tfh cells expressed high levels of both BCL6 and GATA3. By using an inducible deletion of LAT, we showed that Tfh cell differentiation was the result of defective LAT-PLCγ1 signaling, rather than abnormal thymic selection.  In addition, B cells were required for spontaneous development of Tfh cells in these mice. Together, these results demonstrated a novel role for tonic LAT-PLCγ1 signaling in modulating Tfh cell differentiation during development of autoimmune syndrome.