CD4 Effectors must re-encounter Antigen Locally in the Presence of Signals from Infection to Fully Differentiate into Specialized Tissue-restricted TFH and ThCTL effectors

Abstract

Abstract Functionally specialized, tissue-restricted CD4 effector subsets such as T helper cytotoxic cells (ThCTL) in the infected tissue and T follicular helper cells (TFH) in secondary lymphoid organs develop after Th1 and other effectors. Following influenza A virus infection, we find that CD4 effectors must recognize cognate Ag/MHC-II to become ThCTL and TFH but that this does not require a specific APC subset. While intrasplenic and intravenous Ag/APC delivery support spleen TFH, they do not support lung ThCTL or DLN TFH. Conversely, intranasal Ag/APC delivery supports lung ThCTL and DLN TFH indicating that Ag presentation in the site of residence is crucial. Strikingly, we find that continuing Ag-independent signals from infection are also needed for optimal generation of both subsets, even at this late effector phase. This contrasts with CD4 memory generation from effectors which is dependent only on Ag recognition and not on infection. Thus, this implies a pivotal checkpoint at which the fate of CD4 effectors is determined. In the absence of Ag most contract, while Ag alone can generate memory, and with continuing infection-mediated signals, distinct specialized effectors. This guards against unnecessary responses when pathogen is not present or has been cleared, but ensures the development of potent effectors in tissues if it persists. We propose that for vaccines to induce stronger immunity, they will need to be designed to provide additional presentation of CD4 T cell Ag and signals associated with infection at the effector checkpoint. This will provide the TFH needed for strong B cell Ab response and strong tissue-restricted CD4 T cell memory to ensure frontline response and broad, heterosubtypic protection.