2021 – TNFΑ-DRIVEN INTERPLAY BETWEEN HEMATOPOIETIC STEM CELLS AND ANTIGEN-SPECIFIC CYTOTOXIC T CELLS

Clonal expansion of aberrant hematopoietic stem cells (HSCs) underlies many of the hematological disorders. Cells with somatic mutations can be eliminated through presentation of neoantigens on MHC class I to antigen specific CD8+ cytotoxic T lymphocytes (CTL). However, much remains to be elucidated on how HSCs and CTLs interact with each other. Here, we uncover a unique TNFα-driven interplay between HSCs and CTLs. Co-culture and adoptive transfer experiments using ovalbumin-expressing (OVA+) HSCs (Lin-/c-Kit+/Sca-1+/Flk2-/CD48-/CD150+) and OVA-specific OT-I CTLs demonstrated that OVA+ HSCs efficiently present OVA peptide on MHC class I and directly activated OT-I CTLs, making HSCs one of the most susceptible hematopoietic populations to CTL killing. Indeed, adoptive transfer of OT-I CTLs to mixed chimeric mice that harbor both WT and Jak2V617F OVA+ hematopoietic cells specifically eliminated Jak2V617F OVA+ HSC clones and cured myeloproliferative neoplasm. Intracellular FACS analyses revealed that activated OT-I CTLs produced various cytokines including IFNγ and TNFα and HSCs responded to CTL-derived cytokines to upregulate T cell-attracting chemokines such as CXCL9. Interestingly, the response of HSCs to CTL-derived TNFα was critical for CTLs to induce granzyme B, and TNFα receptor–deficient OVA+ HSCs, but not IFNγ receptor–deficient OVA+ HSCs, escaped from OT-I CTL killing. Of note, such response was unique to HSCs and not observed in granulocyte-monocyte progenitors (GMPs: Lin-/c-Kit+/Sca-1-/CD34+/FcγR+). By contrast, prior exposure to TNFα but not IL-1β or IL-6, rendered OVA+ HSCs, but not OVA+ GMPs, resistant to OT-I CTL killing largely through upregulation of PD-L1 and PD-L2. Taken together, our results reveal the robustness of HSC quality control via MHC class I-dependent interplay with CTLs and highlight TNFα as its critical but context-dependent regulator.