Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cell homeostasis and contributes to allergic and inflammatory responses. TSLP can act directly on mouse CD4+ T cells, but in humans, the available data have indicated that TSLP receptors are not expressed on CD4+ T cells and that TSLP instead activates dendritic cells, which in turn promote the proliferation and differentiation of CD4+ T cells. We now unexpectedly demonstrate the presence of TSLP receptors on activated human CD4+ T cells. Strikingly, whereas freshly isolated peripheral blood human T cells show little if any response to TSLP, TCR stimulation allows a potent response to this cytokine. Moreover, TSLP increases the sensitivity of human CD4+ T cells to low doses of IL-2, augmenting responsiveness of these cells to TCR engagement. Our results establish that human CD4+ T cells are direct targets for TSLP.

Cytochrome c-specific CD4 T cells from transgenic donors transferred to syngeneic B10.A mice expand more vigorously upon immunization if exogenous IL-6 is provided during the initial phase of immunization. The resultant increase in the frequency and number of Ag-specific cells is observed in the blood, lymph nodes, spleen, liver, and lung and persists for at least 3 mo. Treatment of immunized recipients with anti-IL-6 or use of IL-6 knockout recipients reduced the frequency of Ag-specific CD4 T cells during a comparable period, indicating that IL-6 is physiologically involved in the expansion of memory and/or effector cells and thus in the persistence of memory. IL-6 did not alter the duration of Ag-presenting activity. Both CFSE dilution studies and labeling with BrdU indicated that IL-6 does not effect proliferative rates of responding CD4 T cells. By contrast, annexin V staining was diminished in responding cells from the IL-6-treated animals, particularly among those cells that had undergone five or more divisions. These results indicate that IL-6 reduces the level of apoptosis among Ag-stimulated cells; thus, it plays a central role in determining numbers of memory and/or effector CD4 T cells in response to immunization over extended periods.