The generation of a robust high-affinity antibody response is the goal of most vaccination strategies against infection. T follicular helper cells play a critical role in provision of help to B cells for the selection of high-affinity B cells in germinal centers (GC). While there is a growing understanding of the signals required to generate Tfh, the signals that position or retain Tfh within the GC are not well understood. Elegant photoactivation studies have revealed that the majority of Tfh cells entering a particular GC stay in that GC long-term. How Tfh persist for many days in the GC is unclear. Identifying signals that regulate Tfh dwell time in individual GCs could be important targets to regulate or boost the positioning of Tfh cells to GCs to facilitate the generation of a robust protective antibody response or limit Tfh in Ab mediated autoimmunity. We have identified an ECM/integrin axis that appears to modulate the association of Tfh with the GC and has a major impact on GC formation and antibody production. The RGD-motif ECM (extracellular matrix) components are highly restricted to the GC upon immune challenge and co-localize with follicular dendritic cells (FDC). Correspondingly, T cells express the matrix-binding integrin ?V?3 that binds to the RDG-motif in ECM components. Integrin ?V deficiency in T cells led to a striking defect in GC development, attenuated GC B cells and reduced antigen-specific IgG to protein immunization and Influenza A infection. Moreover, in the absence of integrin ?V, LLPCs were lost but Bmem remained. The altered B cell response was not associated with a failure of ?V cKO T cells to differentiate into Tfh, but rather, the failure of ?V cKO Tfh to accumulate within the GC. Based on these novel observations, we hypothesize that integrin ?V expression by Tfh cells provides a positioning cue for location to, or retention/survival within, the GC via interaction with FDC- associated ECM. The overall goal is to use this model to define immune mechanisms that influence Tfh positioning or dwell time within the GC and to determine the consequence of Tfh miss-positioning on the developing B cell repertoire.
Specific Aim 1. Integrin ?V regulation of Tfh cell dynamics in germinal genters.
Specific Aim 2. The role of ?V in Tfh fate and function? Specific Aim 3. The consequence of integrin ?V Tfh positioning on the B cell effector fate and repertoire. Knowledge gained on the role of this ECM/integrin axis in Tfh GC support should provide novel targets for the development of vaccines that optimize Tfh help and enhance high affinity antibody production.

Public Health Relevance

High-affinity antibody responses are the goal of most vaccination strategies against infection. We have identified an ECM/integrin axis that appears to modulate the association of follicular helper T cells (Tfh) with the GC and has a major impact on GC formation and antibody production. Knowledge gained on the role of this ECM/integrin axis in Tfh GC support should provide novel targets for the development of vaccines that optimize Tfh help and enhance high affinity antibody production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI136536-01A1
Application #
9661106
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Ferguson, Stacy E
Project Start
2018-11-01
Project End
2023-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627