Should I stay or should I go: The role of costimulatory signals and S1P receptors in CD8+ T cell trafficking

Abstract

Effective infection control relies on the trafficking of T cells within and between lymphoid and non-lymphoid tissues (NLT) through the circulatory blood and lymph. During immune responses, effector CD8+ T cells can emigrate from secondary lymphoid organs (SLO) to join blood circulation, then migrate into inflamed tissues to conduct functions. After the resolution of infections, some effector T cells survive and maintain their migrating lifestyle in the blood and lymphatic systems, becoming recirculating memory cells. Another population of effector T cells adapt to the NLT environment and are maintained locally without recirculating, becoming resident memory cells (Trm).Recirculating and tissue-resident memory CD8+ T cells provide distinct modes of immune protection, yet the signals dictating the differentiation of these populations are ill-defined. In particular, the interactions within tissues that promote the generation of Trm are unclear. In the first part of this thesis, we show that the inducible costimulatory molecule ICOS is required for CD8+ Trm but not recirculating memory subsets. Furthermore, ICOS engagement during CD8+ T cell recruitment to NLT is critical for efficient Trm establishment: ICOS/ICOS-L interactions are dispensable throughout CD8+ T cell priming and for Trm maintenance, while ICOS-L expression by radioresistant cells is key for optimal Trm generation. Together, this part of the data illustrates that specific local costimulatory cues can promote the production of tissue-resident populations, with potential implications for therapeutic manipulation. The second part of this thesis was focused on understanding the mechanisms that regulate CD8+ T cell egress from SLO into the blood. T cell-intrinsic S1PR1 expression is thought to be indispensable for this process in both naïve and effector populations. However, after different infections, we found diverse dependencies on S1PR1-mediated egress from SLO with activated CD8+ T cells. S1PR1 deficient CD8+ T cells can efficiently traffic into the blood after LCMV but not influenza virus infection. The mechanisms that activated CD8+ T cells utilized to emigrate SLO are still in exploration. Our findings contrast with a widely accepted model that envisages S1PR1 expression as a prerequisite for CD8+ T cell trafficking in the blood.