Differential requirements for OX40 signals on generation of effector and central memory CD4⁺ T cells

Memory T cells can be divided into effector memory (T_EM) and central memory (T_CM) 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⁺ T_EM and T_CM cell subsets are unknown. We found that OX40-deficient mice showed a marked reduction in the number of CD4⁺ T_EM cells, whereas the number of CD4⁺ T_CM 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⁺ T_EM, but not the CD4⁺ T_CM population. In a different transfer experiment with in vitro established CD4⁺CD44^highCD62L^low (T_EM precursor) and CD4⁺CD44^highCD62L ^high (T_CM precursor) subpopulations, OX40-KO T _EM precursor cells could not survive in the recipient mice, whereas wild-type T_EM precursor cells differentiated into both T_EM and T_CM cells. In contrast, T_CM precursor cells mainly produced T_CM cells regardless of OX40 signals, implying the dispensability of OX40 for generation of T_CM cells. Nevertheless, survival of OX40-KO T_EM cells was partially rescued in lymphopenic mice. During in vitro recall responses, the OX40-KO T_EM 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⁺ T_EM cells. Collectively, the present results indicate differential requirements for OX40 signals on generation of CD4⁺ T_EM and T_CM cells.