Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers

Abstract

Immunodominance to nonneutralizing epitopes is a roadblock in designing vaccines against several diseases of high interest. One hypothetical possibility is that limited CD4 T cell help to B cells in a normal germinal center (GC) response results in selective recruitment of abundant, immunodominant B cells. This is a central issue in HIV envelope glycoprotein (Env) vaccine designs, because precursors to broadly neutralizing epitopes are rare. Here, we sought to elucidate whether modulating the quantity of T cell help can influence recruitment and competition of broadly neutralizing antibody precursor B cells at a physiological precursor frequency in response to Env trimer immunization. To do so, two new Env-specific CD4 transgenic (Tg) T cell receptor (TCR) mouse lines were generated, carrying TCR pairs derived from Env-protein immunization. Our results suggest that CD4 T cell help quantitatively regulates early recruitment of rare B cells to GCs.

COVID-19 vaccine mRNA-1273 elicits a protective immune profile in mice that is not associated with vaccine-enhanced disease upon SARS-CoV-2 challenge

“…(AIM) assay, which can identify activated cells even if they do not express sufficient cytokine to be measured by traditional ICS methods (Figure 7E; Lee et al, 2021). Antigen-experienced (CD44 + ) T cells were assessed for the upregulation of activation markers CD69 and CD154 (CD40L) following stimulation with S1 and S2 peptide pools in a 6-h culture in vitro.…”

Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine

“…We analyzed antigen-specific T cell responses elicited by pre-F/G vaccination compared to pre-F or Hex G alone, employing an activation-induced marker (AIM) assay in conjunction with peptide pool restimulation over a 6 hour culture period. The AIM assay detects antigen-specific T cells from the endogenous, polyclonal repertoire that upregulate the activation markers CD40L(CD154) and CD69 in response to peptide stimulation ( 63 , 77 ). Peptide libraries (15-mers overlapping by 11 amino acids) spanning the entire ectodomain of the F or G coding regions were used to quantify the F and G-specific responses, not to map specific epitopes.…”

Generation of High Quality Memory B Cells

“…This raised the question of whether this is a simple correlation or a causal association. This issue has been approached in the mouse by employing BCR (VRC01 germline version) knock-in B cells and transgenic TCR T cells ( 59 ). Since, in the case of influenza and HIV bnAb responses, immunodominance is one of the key issues, this study was particularly designed to address whether increasing accessibility to T cell help preferentially enhances the rare immune-subdominant bnAb precursor B cell responses.…”