The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa.

Heather D Marshall,Joe Craft,Susan M Kaech,Matthew M Staron,John P Ray,Nianzhi Zhang,Dipika Gawande,Brian J Laidlaw

doi:10.7554/elife.04851

Heather D Marshall, Joe Craft + Show 6 more

Open Access

https://doi.org/10.7554/elife.04851

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Journal: eLife	Publication Date: Jan 8, 2015
Citations: 99	License type: CC BY 4.0

Affiliation: Yale University, Howard Hughes Medical Institute

Abstract

T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

Highlights

During acute viral infections, CD4 T cells differentiate into primarily T helper 1 (Th1) and T follicular helper (Tfh) effector cells (Marshall et al, 2011; Johnston et al, 2012; Hale et al, 2013)
Because CD4 T helper subsets begin to diverge within the first few days of viral infection (Choi et al, 2013b) and we found fewer Tfh and more Th1 precursor cells in the absence of TGF-β signals during LCMV infection (Figure 2—figure supplement 1A), we questioned when TGF-β was required for Tfh differentiation during influenza virus infection
We demonstrate that T cell-directed TGF-β signals are critical for insulating early effector CD4 T cells from Th1-promoting IL-2 signals, thereby allowing for virus-specific Tfh cell differentiation

Summary

Introduction

CD4 T cells differentiate into primarily T helper 1 (Th1) and T follicular helper (Tfh) effector cells (Marshall et al, 2011; Johnston et al, 2012; Hale et al, 2013). Similar to CD8 T cells, Th1 cells express the transcription factors (TF) T-bet and Blimp, the effector molecules IFN-γ, TNFα, (and in many cases granzyme B [GrzB] and perforin) and migrate to sites of viral replication to eliminate infected cells. Tfh cells express substantially lower levels of T-bet, and instead of Blimp they express the TF Bcl. Tfh precursor cells start to express the TF Bcl and the chemokine receptor CXCR5, as they downregulate CCR7 and P-selectin glycoprotein ligand 1 (PSGL1) (Johnston et al, 2009; Poholek et al, 2010; Choi et al, 2011; Pepper et al, 2011)

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