SARS-CoV-2 infection induces germinal center responses with robust stimulation of CD4 T follicular helper cells in rhesus macaques

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>CD4 T follicular helper (T<jats:sub>fh</jats:sub>) cells are important for the generation of long-lasting and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates T<jats:sub>fh</jats:sub> cells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that, following infection with SARS-CoV-2, adult rhesus macaques exhibited transient accumulation of activated, proliferating T<jats:sub>fh</jats:sub> cells in their peripheral blood on a transitory basis. The CD4 helper cell responses were skewed predominantly toward a T<jats:sub>h</jats:sub>1 response in blood, lung, and lymph nodes, reflective of the interferon-rich cytokine environment following infection. We also observed the generation of germinal center T<jats:sub>fh</jats:sub> cells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies but delayed or absent IgA antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.</jats:p>

SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential

“…We found that SARS-CoV-2-specific CD4+ T cells expressed especially high levels of ICOS, suggesting active helper function of B cells. These findings suggest that SARS-CoV-2-specific cTfh play a key role in effective immunity, and are in line with the observation that the frequency of total cTfh cells increases at the time of SARS-CoV-2 clearance (Thevarajan et al, 2020) and the detection of robust Tfh responses following exposure of rhesus macaques to SARS-CoV-2 (Elzaldi et al, 2020). Interestingly, the SARS-CoV-2-specific cTfh cells we identified exhibit features similar to a population of cTfh shown to be important in the generation of vaccine-induced antibodies against influenza (Bentebibel et al, 2013).…”

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential

“…These findings suggest that SARS-CoV-2-specific cTfh cells play a key role in effective immunity and are in line with the observation that the frequency of total cTfh cells increases at the time of SARS-CoV-2 clearance 4 and detection of robust Tfh cell responses following exposure of rhesus macaques to SARS-CoV-2. 36 Interestingly, the SARS-CoV-2-specific cTfh cells we identified exhibit features similar to a population of cTfh cells shown to be important in generation of vaccine-induced antibodies against the flu. 25 Both express high levels of CXCR5 and ICOS.…”

Antibody isotype diversity against SARS-CoV-2 is associated with differential serum neutralization capacities

“…These results, particularly the presence of individuals with low neutralizing antibodies are interesting as each individual in our cohort has recovered from SARS-CoV-2 infection. This observation suggests that either we missed the period of robust neutralizing antibody production in certain individuals or other mechanisms, such www.nature.com/scientificreports/ as potent SARS-CoV-2 specific T-cell responses [36][37][38][39][40][41][42] , provided effective viral clearance and immunity. Future studies coupling assessment of antibody and T-cell responses with key clinical information (age, sex, severity of symptoms) will be essential to fully understand this complex immune response.…”