The POSH scaffold protein is essential for signal coordination leading to CD8 T cell differentiation and survival

Caitlyn GuldenpfennigYue GuanBela CersiElida LopezEmma TeixeiroMark Daniels^*

• NextGen Precision Health, Molecular Microbiology and Immunology, University of Missouri, Columbia, United States

Upon antigen recognition, naive CD8 T cells must induce c-JUN N-terminal kinase (JNK), NF-κB, and Akt signaling to drive differentiation and generate a heterogeneous effector response. While the roles of these three pathways individually in mediating essential cellular responses for CD8 T cell differentiation are well established, the mechanisms of signal integration and crosstalk between these pathways to produce a diverse and heterogeneous response to infection remain poorly understood. Here, we establish the critical role of the Plenty of SH3 Domains (POSH) scaffold protein in coordinating signals from all three pathways to support CD8 T cell differentiation and fate. Using novel conditional T cell POSH knockout mouse models, we demonstrate that POSH is essential for the proper induction of the JNK, NF-κB, and Akt pathways. Furthermore, the absence of these signals via POSH leads to reduced differentiation into short-lived effector cells (SLECs), delayed proliferation, and decreased survival of memory precursors (MPECs) during contraction. Collectively, these data identify POSH as a key regulator of CD8 T cell fate and enhance our understanding of the complex mechanisms governing signal integration during CD8 T cell responses to infection.