Local Antigen Encounter and a Type I IFN-IL-15 Axis Cooperatively Program Cytotoxic CD4 Differentiation and Tissue Residency 2261140

Abstract Introduction Cytotoxic CD4 T cells (ThCTL) are a distinct tissue-resident effector subset driving MHC-II- restricted cytotoxicity against pathogens and tumors. They become especially important when pathogens evade immune clearance by downregulating MHC-I. Methods We used a model of influenza infection to define the requirements for differentiation of early CD4 effectors into ThCTL, in the lung, post influenza infection. Results Differentiation into lung ThCTL requires effectors to recognize cognate antigen/MHC-II, locally in the lung, at 6-8 days post-infection (dpi). Various antigen presenting cell subsets can drive ThCTL differentiation but CD28 co-stimulation is not needed and may even attenuate it, which contrasts to T follicular helper (TFH) differentiation. Sustained antigen-independent signals from infection are also crucial throughout the effector phase. We find that infection-induced type I IFN induces IL-15 production, which is essential for supporting development of lung tissue-resident ThCTL. Preliminary data suggest that this represents a stage in the progression of ThCTL effectors into lung CD4 tissue-resident memory (TRM) cells which can provide long-term memory against respiratory infections. While local antigen presentation and IL-15 are traditionally linked to the development of TRM, our findings show that this programming is initiated at this effector checkpoint, determining their fate as TRM. Conclusion This requirement for antigen and infection signals at 6-8 dpi aligns with an effector checkpoint controlling the fate decisions for CD4 memory, TFH and ThCTL. We therefore suggest that vaccines deliver localized antigen and infection-associated signals during this window, to induce the development of protective immunity. Our findings propose a paradigm wherein stringent requirements at this effector checkpoint guard against unnecessary cytotoxic responses if the pathogen has been cleared but ensure the development of potent tissue-restricted immunity if it is still a threat. Funding Source American Lung Association Catalyst Award, R21AI175883 Topic Categories Mucosal and Regional Immunology (MUC)