IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection

PLOS ONE, Dec 2019

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.

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IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection

Braciale TJ (2014) IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection. PLoS ONE 9(9): e105872. doi:10.1371/journal.pone.0105872 IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection Jae-Kwang Yoo 0 Thomas J. Braciale 0 Jo rg Hermann Fritz, McGill University, Canada 0 1 Inflammation Research, Amgen Inc., Seattle, Washington, United States of America, 2 Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America, 3 Department of Microbiology, University of Virginia, Charlottesville, Virginia, United States of America, 4 Department of Pathology, University of Virginia , Charlottesville, Virginia , United States of America 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-a 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. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by U.S. Public Health Service grants AI-15608, HL-33391, AI-37293 and U19 AI-083024 to T.J.B. and Senior Research Training Fellowship from American Lung Association to J.K.Y. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Amgen Inc. provided support in the form of salary for author Jae-Kwang Yoo, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the author contributions section. Competing Interests: The first author, Jae-Kwang Yoo, is currently employed by a commercial company Amgen Inc. However, there are no patents, products in development or marketed products to declare. Therefore, this does not alter the authors adherence to PLOS ONE policies on sharing data and materials. 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 ultimately resulting in germinal center (GC) formation within B cell follicles. The GC response is particularly pronounced due to the inflammatory stimulus produced by the invading microorganisms. 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. Hence, the GC response not only contributes to pathogen clearance but also plays a pivotal role in preventing subsequent infections with the infecting microorganism [15]. 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) [4,610]. The factors controlling TFH differentiation are not as yet fully understood, and multiple cell types and molecules have been implicated in this process [4,6]. IL-21 was initially proposed as a key soluble factor driving the differentiation of Ag-primed CD4+ T cells along the TFH lineage pathway [8,11], and is now recognized as promoting an optimal TFH response [12,13]. However, the mechanism(s) by which IL-21 optimizes the TFH response has not as yet been clearly defined. Recently, we have identified a novel immune cell population in virus infected murine lungs with migratory properties and antigen presenting capacity, the late activator antigen presenting cell (LAPC) [14]. The mPDCA1+CD11c2B2202TcRb2 LAPCs initiate their migration out of the IAV-infected lungs into the draining lymph nodes relatively late in t (...truncated)


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Jae-Kwang Yoo, Thomas J. Braciale. IL-21 Promotes Late Activator APC-Mediated T Follicular Helper Cell Differentiation in Experimental Pulmonary Virus Infection, PLOS ONE, 2014, 9, DOI: 10.1371/journal.pone.0105872