SARS-CoV-2 induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques

Yashavanth Shaan Lakshmanappa,Nam K Tran,Justin C Smith,Anil Verma,Timothy D Carroll,Jesse D Deere,Daniela Weiskopf,J Rachel Reader,Graham Simmons,Michael P Busch,Sergej Franz,Sonny R Elizaldi,Joseph Dutra,Jodie Usachenko,Stephen J Mcsorley,Pamela A Kozlowski,Katherine J Olstad,Jamin W Roh,Alessandro Sette,Jennifer Watanabe,Christopher J Miller,Ramya Immareddy,Koen K A Van Rompay,John H Morrison,Mars Stone,Yee Jurng-Jae ,Dennis J Hartigan-O’connor ,Ngoc Thi Bich Nguyen ,Rebecca L Sammak ,Kourtney Weaver ,Brian Schmidt ,Min Zhong ,Smita S Iyer

doi:10.1038/s41467-020-20642-x

Abstract

CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center (GC) response is an important question as we investigate vaccine induced immunity against COVID-19. Here, we report that SARS-CoV-2 infection in rhesus macaques, either infused with convalescent plasma, normal plasma, or receiving no infusion, resulted in transient accumulation of pro-inflammatory monocytes and proliferating Tfh cells with a Th1 profile in peripheral blood. CD4 helper cell responses skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. SARS-CoV-2 Infection induced GC Tfh cells specific for the SARS-CoV-2 spike and nucleocapsid proteins, and a corresponding early appearance of antiviral serum IgG antibodies. Collectively, the data show induction of GC responses in a rhesus model of mild COVID-19.

Highlights

CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections
Because healthy rhesus macaques infected with SARS-CoV-2 resist immediate re-challenge with the virus[22,23,24], we hypothesized that understanding the CD4 T follicular helper cells (Tfh) and germinal center (GC) response following exposure to SARS-CoV-2 will provide a framework for understanding immune mechanisms of protection
Plasma infusion did not impact viral loads, we report that following infection with SARS-CoV-2, adult rhesus macaques exhibited transient accumulation of activated, proliferating Tfh cells with a Th1 profile in their peripheral blood

Summary

Introduction

CD4 T follicular helper (Tfh) cells are important for the generation of durable and specific humoral protection against viral infections. Studies in humans demonstrate induction of Tfh cells in COVID-19 patients[14,15,16], the impact of SARS-CoV-2 infection on the generation of GC Tfh cells is currently unknown This is a detrimental gap in knowledge as understanding early correlates of durable antibodies, those that circulate in peripheral blood, will aid in the ultimate selection of effective vaccine candidates. Because healthy rhesus macaques infected with SARS-CoV-2 resist immediate re-challenge with the virus[22,23,24], we hypothesized that understanding the CD4 Tfh and GC response following exposure to SARS-CoV-2 will provide a framework for understanding immune mechanisms of protection We tested this hypothesis in the setting of a study designed to examine the therapeutic efficacy of convalescent plasma infusion in curbing a nascent infection. The comprehensive immune analysis in a controlled animal model of mild diseases adds to our understanding of immune responses to SARS-CoV-2

Methods

Results

Conclusion