Date of Award
Spring 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Eisenbarth, Stephanie
Abstract
T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. Indeed, we found by epitope mapping and BCR sequencing that Tfh cells focused the B cell response and therefore, in the absence of Tfh cells, a more diverse clonal repertoire was maintained. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.Furthermore, we sought to reconcile the roles of Tfh cell-derived IL-4 as both a pro-survival factor for highly proliferative GC B cells as well as a switch factor for IgE and IgG1. Due to its potent effects on B cell proliferation and differentiation, IL-4 is considered a canonical Tfh cell cytokine, produced even during antimicrobial responses that elicit little IgG1 and no IgE. However, given that IL-4 is also a switch factor that is sufficient for IgE induction, this raises the question of how Tfh cells produce IL-4 during type 1 immune responses without aberrantly inducing IgE. We first clarified the role of Tfh cell-derived IL-4 during type 1 immune responses, finding that it was required for IgG1 switching in response to immunization with lipopolysaccharide and haptenated protein antigen as well as influenza A virus infection; however, GC B cell formation and plasmablast differentiation were unaffected by the loss of IL-4 from Tfh cells. In addition, we found that Tfh cells during type 1 immune responses generated minimal IL-4 protein, with levels of IL-4 tightly regulated by both transcriptional and post-transcriptional mechanisms. These data support the role of Tfh cell-derived IL-4 as a rheostat for the appropriate induction of IgG1 versus IgE antibodies during type 1 and type 2 immune responses, rather than as a pro-survival factor for GC B cells. Finally, when public health officials raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating COVID-19 at the start of the pandemic, we sought to determine whether and how NSAIDs could affect COVID-19 pathogenesis. NSAIDs affect the production of prostaglandins, which play diverse biological roles in homeostasis and inflammatory responses. Thus, it is plausible that NSAIDs could affect COVID-19 pathogenesis in multiple ways, including modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; regulating replication of SARS-CoV-2 in host cells; and modulating the immune response to SARS-CoV-2. We found that NSAID treatment had no effect on ACE2 expression, viral entry, or viral replication. However, NSAIDs did affect the immune response to SARS-CoV-2 by impairing the production of proinflammatory cytokines as well as early neutralizing antibodies. Our findings therefore indicate that NSAID treatment may affect COVID-19 outcomes by dampening the inflammatory response and the production of protective antibodies, which also has implications for NSAID use during SARS-CoV-2 vaccination.
Recommended Citation
Chen, Jennifer Shuen, "T Cell Regulation of Antibody Responses to Infection and Immunization" (2022). Yale Graduate School of Arts and Sciences Dissertations. 573.
https://elischolar.library.yale.edu/gsas_dissertations/573
