The Role of IL-12 and IL-23 in the Generation and Maintenance of Memory CD4+ T Cells.

Human memory CD4+ T cells can be distinguished from antigenically-naïve CD4+ T cells based on their CD45RA^lowCD45R0^high and CD45RA^highCD45R0^low surface phenotypes, respectively. Memory CD4+ T cells from adult peripheral blood can be further divided based on surface expression of the CCR7 chemokine receptor. Th1 memory CD4+ T cells that are CCR7^high (putative central memory cells or T_cm) are expected to be preferentially targeted to peripheral lymph nodes where the ligands for CCR7 are expressed in high amounts. These cells have been reported to lack expression of the CCR3 and CCR5 chemokine receptors, which facilitate entry into inflamed tissues, and produce little or no interferon (IFN)-γ after stimulation via the αβ-TCR/CD3 complex. CD45RA^lowCD45R0^highCCR7^low CD4+ T cells account for virtually all IFN-g production by human CD4 T cells after ab-TCR/CD3 stimulation using monoclonal antibodies, and for this reason were termed effector memory cells (T_em). These findings, as well as the observation of shorter telomere lengths for memory CD4+ T cells that are CCR7^low compared to those that CCR7^high suggest that the T_cm population may be an intermediate between naïve CD4+ T cells and T_em. It has recently been proposed that the level of signal strength and γc containing cytokines play a role in memory T cell generation. However, little is known whether IL-12 or IL-23 are necessary and for this differentiation and/or maintenance. Our laboratory has previously described a patient with IL-12Rβ1 deficiency, which ablates both IL-12 and IL-23 signaling. This patient had a deficiency in T_em number and function, unexpectedly suggesting that IL-12 and/or IL-23 may play a key role in this process. We therefore hypothesized that signaling through IL-12Rβ1 plays a key role in the latter stages of generation and/or maintenance of human memory CD4+ T cells. Preliminary data thus far show CCR7 expression to be slightly decreased on activated T_cm in response to incubation with IL-2 or IL-12 alone, and to a greater extent with IL-2 and IL-12 incubated together. In addition, spontaneous apoptosis of both T_cm and T_em is decreased upon incubation with IL-12. Taken together, these data suggest that IL-12 may play a role in both generation of T_em and maintenance of both T_cm and T_em.