Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses

Jialong Yang,Hai-Hui Xue,Hongxiang Huang,Yun Pan,Pengcheng Chen,Xingguang Lin,Xiao-Ping Zhong,Jinli Wang,Jimin Gao

doi:10.7554/elife.17936

Jialong Yang, Hai-Hui Xue + Show 7 more

Open Access

https://doi.org/10.7554/elife.17936

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Abstract

T follicular helper (Tfh) cells play critical roles for germinal center responses and effective humoral immunity. We report here that mTOR in CD4 T cells is essential for Tfh differentiation. In Mtorf/f-Cd4Cre mice, both constitutive and inducible Tfh differentiation is severely impaired, leading to defective germinal center B cell formation and antibody production. Moreover, both mTORC1 and mTORC2 contribute to Tfh and GC B cell development but may do so via distinct mechanisms. mTORC1 mainly promotes CD4 T cell proliferation to reach the cell divisions necessary for Tfh differentiation, while Rictor/mTORC2 regulates Tfh differentiation by promoting Akt activation and TCF1 expression without grossly influencing T cell proliferation. Together, our results reveal crucial but distinct roles for mTORC1 and mTORC2 in CD4 T cells during Tfh differentiation and germinal center responses.

Highlights

T follicular helper (Tfh) cells belong to a special subset of CD4 T cells that are essential for germinal center (GC) formation, Ig-class switch and hypermutation, memory B cell and long-lived plasma cells generation, and establishment of long-term protective immunity (King, 2009; Tangye et al, 2013; Craft, 2012; Crotty, 2014; Vinuesa et al, 2016)
Using mice selectively deficient of mechanistic target of rapamycin (mTOR), regulatory-associated protein of mTOR (Raptor)/mTORC1, and rapamycin-insensitive companion of mTOR (Rictor)/mTORC2 in T cells, we report here that mTOR deficiency caused severe decreases in constitutive Tfh and GC-B cells in the mesenteric lymph nodes and Peyer’s patches (PPs), correlated with drastic decreases in virtually all serum IgG subtypes in unchallenged naıve mice
Another study has found that a hypomorphic mutation of mTOR reduces Tfh and GC responses in mice immunized with sheep red blood cells, concluding that mTOR promoted Tfh differentiation (Ramiscal et al, 2015)

Summary

Introduction

T follicular helper (Tfh) cells belong to a special subset of CD4 T cells that are essential for germinal center (GC) formation, Ig-class switch and hypermutation, memory B cell and long-lived plasma cells generation, and establishment of long-term protective immunity (King, 2009; Tangye et al, 2013; Craft, 2012; Crotty, 2014; Vinuesa et al, 2016). TCF1 and LEF1 transcription factors regulate the expression of multiple genes such as ASCL2, Blimp1-Bcl-6 axis, IL6Ra, gp130, and ICOS that are involved in Tfh differentiation (Choi et al, 2015; Liu et al, 2014; Xu et al, 2015). MTOR-deficient CD4 T cells fail to differentiate to Tfh cells following antigen immunization, resulting in impaired GC-B cell formation and antigen-specific IgG responses. Both mTORC1 and mTORC2 contribute significantly to Tfh differentiation but appear to do so via distinct mechanisms. MTORC2-deficient CD4 T cells do not display obvious impairment in proliferation; instead, they display impaired Akt activation because of decreased phosphorylation at S473, subsequently increased cell death, impaired GSK3b phosphorylation at S9 and inactivation, and decreased b-catenin and TCF1 expression. Overexpression of a phosphomimetic mutant of Akt, Akt S473D, or TCF1 can partially restore Tfh differentiation, suggesting an mTORC2/Akt/TCF1 axis for Tfh differentiation

Results

Discussion

Materials and methods