T cell intrinsic TCF-1 dictates lung tissue resident T cell help to local memory B cell response during influenza infection 3899

Description Current influenza (flu) vaccination strategies rely on accurate prediction of the circulating strains for the upcoming season. Therefore, the induction of a durable, cross-reactive memory response is desirable. Flu infection induces cross-reactive tissue resident memory T (Trm) and B (Brm) cells which rapidly respond to reinfection. Tissue resident helper (Trh) cells are a population T follicular helper (Tfh)-like CD4+ Trm cells that promote the development of Brm cells. The transcription factor TCF-1, encoded by Tcf7, is critical in the development of Tfh cells, however its role in Trh cell development and lung humoral immunity is unknown. Utilizing a Tcf7fl/flCD4Cre mouse model, we found T cell-intrinsic TCF-1 is required for the development of flu-specific Trh cells and Brm cells during primary infection. In Tcf7fl/flCD4Cre mice, influenza HA-specific IgG and IgA antibody titers waned significantly within six months of primary infection, leading to reduced protection against homosubtypic reinfections. During heterosubtypic reinfection, Tcf7fl/flCD4Cre mice displayed increased viral load, associated with a reduced influenza nucleocapsid-specific T cell and antibody secreting cell response in the lungs. Together, our data indicates that T cell-intrinsic TCF-1 is required for durable mucosal immunity following flu infection, including lung cellular and humoral immunity to variable and conserved antigens, which may provide insight into universal flu vaccine development. Funding Sources NIH/NIAID R01 AI151139 AAUW Research Publication Grants in Engineering, Medicine and Science Topic Categories Mucosal and Regional Immunology (MUC)