Contribution of 4-1BBL on radioresistant cells in providing survival signals through 4-1BB expressed on CD8⁺ memory T cells in the bone marrow

Abstract

The persistence of memory lymphocytes is a critical feature of adaptive immunity. The TNF family ligand 4-1BBL supports the antigen-independent survival of CD8⁺ memory T cells. Here, we show that mice lacking 4-1BB only on αβ T cells show a similar defect in CD8⁺ T-cell recall responses, as previously shown in 4-1BBL-deficient mice. We show that 4-1BB is selectively expressed on BM CD8⁺ but not CD4⁺ memory T cells of unimmunized mice. Its ligand, 4-1BBL, is found on VCAM-1⁺ stromal cells, CD11c⁺ cells, and a Gr1(lo) myeloid population in unimmunized mice. Adoptive transfer of in vitro generated memory T cells into mice lacking 4-1BBL only on radioresistant cells recapitulates the defect in CD8⁺ T-cell survival seen in the complete knockout mice, with smaller effects of 4-1BBL on hematopoietic cells. In BM, adoptively transferred DsRed CD8⁺ memory T cells are most often found in proximity to VCAM-1⁺ cells or Gr1⁺ cells, followed by B220⁺ cells and to a much lesser extent near CD11c⁺ cells. Thus, a VCAM-1⁺CD45(-) stromal cell is a plausible candidate for the radioresistant cell that provides 4-1BBL to CD8⁺ memory T cells in the BM.