CD127 and Sca1 mark self-driven memory-phenotype CD4⁺ T cells that differ from foreign antigen-specific memory cells and possess inflammatogenic and anti-tumor activities

Abstract Under steady-state conditions, conventional CD4 +T lymphocytes are divided into naïve (CD44 loCD62L hi) and memory (CD44 hiCD62L lo) cell compartments. While the latter population is presumed to comprise a mixture of explicit foreign antigen (Ag)-specific “authentic” memory and foreign Ag-independent memory-phenotype (MP) cells, phenotypic markers differentially expressed in these two cell types have yet to be identified. Moreover, it is unknown whether MP cells consist of distinct subsets defined by marker expression. In this study we demonstrate using combined single cell RNA sequencing and flow cytometric approaches that self-driven MP CD4 +T lymphocytes are divided into CD127 hiSca1 lo, CD127 hiSca1 hi, CD127 loSca1 hi, and CD127 loSca1 losubpopulations that are Bcl2 lowhile foreign Ag-specific memory cells are CD127 hiSca1 hiBcl2 hi. We further show that amongst the four MP subsets, CD127 hiSca1 hilymphocytes represent the most quiescent, cell division-experienced subpopulation derived from peripheral naïve precursors. Finally, we provide new evidence arguing that the CD127 hiSca1 hiMP subpopulation tonically expresses T-bet and possesses the capacity to trigger systemic inflammation including colitis, interstitial pneumonia, and nephritis as well as to exert anti-tumor activity against malignant lymphoma. Together our findings define MP CD4 +T lymphocytes as a unique, self-driven population consisting of distinct subsets that differ from conventional foreign Ag-specific memory cells in marker expression and reveal the inflammatogenic nature of the mature CD127 hiSca1 hiMP cells.