Spontaneous Differentiation of T Follicular Helper Cells in LATY136F Mutant Mice

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 overproduction of Th2 cytokines, 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 in the LATY136F mice using the KN2 reporter mice, in which human CD2 expression marks T cells that are actively producing IL4 protein. We showed that these mice had spontaneous Tfh differentiation. Despite the fact that the majority of CD4+ T cells were skewed to Th2 and were GATA3+, only a small subset of them 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 LAT conditional knockout mice that inducibly express only the LATY136F allele, we further showed that Tfh cell differentiation was likely the result of defective LAT-PLCγ1 signaling in the periphery. In addition, B cells were required for spontaneous development of Tfh cells and uncontrolled T cell expansion in these mice. Together, these results indicated a novel role for tonic LAT-PLCγ1 signaling in modulating Tfh cell differentiation during development of autoimmune syndrome.

Imbalance of helper T cell type 1, helper T cell type 2 and associated cytokines in patients with systemic lupus erythematosus: A meta-analysis

“…SLE is characterized by polyclonal activation of B cells, which leads to the production of autoantibodies and pathological damage. Several cytokines secreted by Th2 cells promote the production of B cell antibodies ( O'Brien et al, 2021 ). There is evidence that a negative feedback between Th1-type and Th2-type immune responses regulates normal immune balance.…”

Aberrant B Cell Signaling in Autoimmune Diseases

“…On the other hand, spontaneous GCs can also originate from defects in T cells, such as the pathogenic accumulation of Tfh cells induced by IFNγ excess in the sanroque lupus model [ 100 ] or aberrant production of IL-17 [ 101 ]. Moreover, aberrant signaling in T cells has been implicated in autoimmunity, for example, a deficiency for the mTOR inhibitor Tsc1 [ 102 ] or a mutation in the phospholipase Cγ1 (PLCγ1)-binding site of linker for activation of T cells (LAT), downstream of the T cell receptor [ 103 ].…”

ZAP70, too little, too much can lead to autoimmunity*

“…Additionally, considering the similarities between the Y136F murine 70,[118][119][120][121] and the partially truncated LAT caused autoimmune phenotypes in patients, 113 one could speculate that the analogous human and murine tyrosines in LAT that bind PLCγ1 may promote some similar essential signaling function in controlling T cell quiescence. We recently showed that the phosphorylation kinetics of Y136/Y132 play a critical role in supporting T cell self and nonself-ligand discrimination.…”

“…This finding was surprisingly similar to a mutant mouse line in which the Y136 residue was substituted with a phenylalanine (LAT‐Y136F mice; murine Y136 corresponds to human Y132, Figure 5). 70,118‐121 The Y136F mutation abrogated calcium mobilization, PLCγ1 signals, and NFAT signals in the mutant T cells, thereby disrupting normal T cell thymic development. Nonetheless, the lymphopenia conditions in Y136F mice could result in Th2‐biased lymphoproliferation, spontaneous follicular helper T cell development, and autoimmune nephritis and fibrosis 69,70,118,122‐124 …”