Exploration Of Roles Of Cd4 T Cell Help In Recruitment Of Rare B Cells To Germinal Centers

Abstract The elicitation of broadly neutralizing antibody (bnAb) responses is a major goal for developing an efficacious HIV vaccine. The HIV Env trimer is a weak immunogen, but it will be a necessary component in a HIV vaccine immunization schedule to drive affinity maturation to bnAbs. There are substantial biological challenges; bnAb precursor B cells are rare in humans, and B cell responses are typically directed to non-neutralizing immunodominant Env epitopes. HIV bnAb development relies heavily on germinal centers (GC) for affinity maturation. The survival of GC B cells is dependent on help from follicular helper CD4 T cells (TFH). Here, we have studied whether the modulation of TFH cells affect B cell immunodominance and competitiveness of rare B cells. We generated Env-specific TCR transgenic mice specific for a I-Ab MHCII epitope we mapped in Env. By utilizing our previously defined VRC01gHL B cell transfer model (Abbott et al., Immunity 2018), combined with co-transfer of CD4 T cells from our new Env-specific TCR transgenic mouse, we examined the competitive fitness of VRC01gHL B cells responding to Env antigens engineered to exhibit varying affinities for VRC01gHL. Increased availability of Env-specific CD4 T cells accelerated the initial expansion of GC VRC01gHL cells in response to a high affinity immunogen. However, improvements in early GC VRC01gHL cells were not observed for low affinity Env trimer immunogens. We are actively exploring whether slow delivery immunization strategies (Cirelli et al., Cell 2019) enhance the ability of Env-specific CD4 T cells to recruit rare VRC01-class B cells to GCs in mice.