Differential Requirements for OX40 Signals on Generation of Effector and Central Memory CD4+ T Cells

Publisher Website
Google Scholar
Abstract
Memory T cells can be divided into effector memory (TEM) and central memory (TCM) subsets based on their effector function and homing characteristics. Although previous studies have demonstrated that TCR and cytokine signals mediate the generation of the two memory subsets of CD8+ T cells, the mechanisms for generation of the CD4+ TEM and TCM cell subsets are unknown. We found that OX40-deficient mice showed a marked reduction in the number of CD4+ TEM cells, whereas the number of CD4+ TCM cells was normal. Adoptive transfer experiments using Ag-specific CD4+ T cells revealed that OX40 signals during the priming phase were indispensable for the optimal generation of the CD4+ TEM, but not the CD4+ TCM population. In a different transfer experiment with in vitro established CD4+CD44highCD62Llow (TEM precursor) and CD4+CD44highCD62Lhigh (TCM precursor) subpopulations, OX40-KO TEM precursor cells could not survive in the recipient mice, whereas wild-type TEM precursor cells differentiated into both TEM and TCM cells. In contrast, TCM precursor cells mainly produced TCM cells regardless of OX40 signals, implying the dispensability of OX40 for generation of TCM cells. Nevertheless, survival of OX40-KO TEM cells was partially rescued in lymphopenic mice. During in vitro recall responses, the OX40-KO TEM cells that were generated in lymphopenic recipient mice showed impaired cytokine production, suggesting an essential role for OX40 not only on generation but also on effector function of CD4+ TEM cells. Collectively, the present results indicate differential requirements for OX40 signals on generation of CD4+ TEM and TCM cells.