Differential IL-2 Expression by Effector CD8 T cells and Fate Determination

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ABSTRACT A signature of polyfunctional, long-lived memory CD8 T cells, IL-2 production capability is believed to be largely downregulated in effector CD8 T cells. Using novel phenotypic markers that distinguish effector cytotoxic T lymphocytes (CTLs) into memory-fated (memory precursor effector cell, MPEC) and terminally differentiated (short-lived effector cell, SLEC) subsets, our studies were the first to establish that memory CD8 T cells retain the ability to produce copious amounts of IL-2 throughout differentiation; even during the effector phase. We found that MPECs are capable of robust IL-2 production alongside vigorous production of effector molecules (granzyme B, IFN-γ and TNF-α). This was surprising since naïve CD8 T cells are believed to largely lose IL-2 production capability after activation and effector differentiation. Using murine models of conditional il2 ablation in a subset of antigen-specific CD8 T cells, we have further discovered that autocrine IL-2 is functionally relevant, and is needed during primary responses (and not during secondary responses) to imprint the hallmark memory property of potent recall expansion and protection against secondary challenge. Intriguingly, IL-2-sufficient MPECs transduce paracrine IL-2 signals less efficiently than their IL-2 non- producing SLEC counterparts. SLECs do not make IL-2, but receive strong paracrine IL-2 signals through increased expression of the high affinity IL-2R, and expand to ~10-fold higher numbers than MPECs. We hypothesize that autocrine IL-2 signaling in MPECs versus strong paracrine IL-2 signals in SLECs institute qualitatively distinct gene expression programs, thus resulting in their starkly disparate life versus death fates. Alternatively, it is possible that despite retaining the ability for IL-2 production, MPECs in actuality do not produce IL-2 in vivo, thus undergoing lesser expansion and preserving their memory fitness for recall expansion. Much of our understanding of the role of IL-2 in CD8 T cell fate determination comes from in vitro assessment of IL-2 production after restimulation of MPECs and SLECs, or through genetic ablation of IL-2. Hence, the ontogeny of IL-2 production capable MPECs and IL-2 non-producing SLECs remains ill-defined vis a vis their history of in vivo IL-2 production, and is confounded by thymic developmental effects or autoimmune side effects of germline il2 ablation. In this exploratory R21 proposal we have generated unique murine models of conditional il2 gene deletion (for specific ablation of autocrine IL-2 in post-thymic T cells), and IL-2 reporter system (for in vivo tracking of IL-2 production history of antigen-specific CD8 T cells). Using these innovative tools, we seek to resolve the enigma of how autocrine and paracrine IL-2 signals determine the polar life versus death decisions of MPECs and SLECs. Illumination of the signaling and transcriptional cascades downstream of autocrine and paracrine IL-2 signals may be exploited for innovating novel pharmacologic or immunologic interventions to shift the balance of effector and memory CTLs as defined by clinical needs.