IL-21 promotes late activator APC-mediated T follicular helper cell differentiation in experimental pulmonary virus infection.

Jae-Kwang Yoo,Thomas J Braciale,Jörg Hermann Fritz

doi:10.1371/journal.pone.0105872

Jae-Kwang Yoo, Thomas J Braciale + Show 1 more

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https://doi.org/10.1371/journal.pone.0105872

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Journal: PloS one	Publication Date: Sep 24, 2014
Citations: 5	License type: CC BY 4.0

Affiliation: University of Virginia, Carter Center

Abstract

IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and TFH cells, IL-21 plays a pivotal role in promoting TFH differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes TFH differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified TFH inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates TFH differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of TFH responses during respiratory virus infection.

Highlights

Following infection with pathogenic microorganisms, the encounter of B cells with their cognate specific Ag in secondary lymphoid organs triggers B cell activation, proliferation and differentiation resulting in germinal center (GC) formation within B cell follicles
To characterize T follicular helper cell response to primary influenza A virus (IAV) infection at a mucosal tissue i.e. the respiratory tract, we examined the kinetics of generation and accumulation of TFH T cells in the draining mediastinal lymph nodes of C57BL/6 mice intranasally (i.n.) infected with a sub-lethal dose (0.05LD50) of A/PR/ 8/34 virus
IL-21 receptor signaling modulates late activator antigen presenting cell (LAPC) migration from lung tissue into the draining lymph nodes (dLN) of IAV-infected mice Since in the mixed bone marrow (BM) chimera the absence of the IL-21R on the responding anti-viral CD4+ T cells did not diminish the generation of CD4+ TFH T cells in the dLN but the kinetics of IL-21 expression paralleled with LAPC accumulation in the dLNs, we considered the possibility of IL- 21 expression and FACS-analysis

Summary

Introduction

Following infection with pathogenic microorganisms, the encounter of B cells with their cognate specific Ag in secondary lymphoid organs triggers B cell activation, proliferation and differentiation resulting in germinal center (GC) formation within B cell follicles. GC B cell responses and GC formation is largely T cell dependent. Hallmarks of the GC response include BcR affinity maturation, plasma cell differentiation and the generation of memory B cells. TFH T cells are recently recognized as a distinct CD4+ T cell subset defined as PD1+CXCR5+Bcl-6+. This T-cell subset has been implicated as a key regulator of the GC B cell response through the delivery of multiple soluble and cell-associated signals to GC B cells including the production of soluble factors (IL-4 and IL-21) and the display of co-stimulatory ligands and receptors (ICOS, CD28, CD40L and CD84) [4,6,7,8,9,10]

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