Sex differences in a cytokine controlling antibody class switch recombination - Project Summary This is an R21 application from Dr. Daniel Lingwood (PI), an Associate Professor of Medicine at the Ragon Institute of Mass General, MIT and Harvard, whose research program defines fundamental rules of B cell ‘decision making’ to inform antibody vaccine design. His laboratory has developed and tested leading structure- based candidate universal influenza vaccine immunogens within purpose-built transgenic mouse vaccine models that recapitulate human antibody diversity and development. This has culminated in Dr. Lingwood’s principle of ‘pathway-amplification’, wherein natural antibody gene-hardwired antigen-target solutions can be accessed and expanded by rationally designed vaccines. In this application, Dr. Lingwood proposes to mechanistically define how B cell class switch recombination (CSR), a core immune reaction underscoring all humoral immunity (e.g. IgM -> IgG), is modulated by sex differences in hormones and circulating cytokines. Adaptive immunity, including the generation of IgG, is often elevated in females, however mechanistic reasons are lacking. In preliminary data, Dr. Lingwood finds that the circulating levels of APRIL, a cytokine that stimulates CSR independently of conventional T cell help, is lower in male compared female mice. Antibody responses to T cell/thymus- independent (TI) antigens (non-protein pathogen features such as bacterial glycan polymers and lipids) are dependent on ligation of the APRIL receptor TACI and Dr. Lingwood shows that IgG switching within this pathway is correspondingly higher in females. The sex differences in both APRIL and IgG switching can be reversed by male gonadectomy (GDX) to remove circulating testosterone. Dr. Lingwood will now test the central hypothesis that testosterone suppresses APRIL, lowering the class switched IgG in response. In Aim 1, Dr. Lingwood will apply molecular tools to modulate the circulating concentration of APRIL and testosterone in mice to assess hormone feedback on APRIL and ultimate control over IgG switching within the TACI-dependent TI-response pathway. In Aim 2, Dr. Lingwood will deploy a model of bone marrow chimerism his laboratory has developed to stably engraft the host lymphoid organs with sex-mismatched CD45+ leukocytes (macrophages, granulocytes, monocytes and T and B lymphocytes). This system will experimentally distinguish cell intrinsic (e.g. XX vs XY) from environmental (testis vs ovary vs APRIL) contributions to sex differences in antibody CSR in vivo. Collectively this proposal aims to rigorously define a new mechanism for sex-based control over a core immune reaction that is at the foundation of humoral immunity.
