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-deticient mice showed a marked reduction in the number of CD4(+) TEM cells, whereas the number of CD4(+) T,m 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(+) T-CM population. In a different transfer experiment with in vitro established CD4(+)CD44(high) CD62(low) (T-EM precursor) and CD4(+)CD44(high) CD62L(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,m 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(+) T-EM and T-CM cells.