11-12 Effector T cells can be activated to release cytokines independently of antigen recognition.
As we have seen, a central paradigm in adaptive immunity is the requirement for antigen recognition by the cognate receptors of naive lymphocytes to induce their differentiation into mature effector cells. However, effector T cells also acquire the ability to be activated by pairs of cytokines, independently of antigen recognition by their T-cell receptor. The cytokine pairs that mediate this ‘noncognate’ function of differentiated effector cells appear to be the same as those that activate the ILC subset that parallels each T-cell subset (Fig. 11.19). And in each case, the pair of stimulating cytokines includes one cytokine that activates a receptor that signals via a STAT factor, and one that activates a receptor that signals via NFκB—typically a member of the IL-1 receptor family. Thus, for both TH1 cells and ILC1 cells, stimulation by IL-12 (STAT4) plus IL-18 induces production of IFN-γ. Similarly, stimulation of TH2 and ILC2 cells by TSLP (STAT5) plus IL-33 produces IL-5 and IL-13, and both TH17 and ILC3 cells stimulated by IL-23 (STAT3) plus IL-1 produce IL-17 and IL-22. In this way, mature effector CD4 T cells acquire innate-like functional properties that allow them to amplify different types of immune responses without the requirement for antigen recognition. Note that in the case of type 1 and type 3 cells, the IL-1 family member involved (IL-18 and IL-1, respectively) is produced by inflammasome activation in myeloid cells. Conversely, IL-33,
TH1 cells protect Rag2-defcient mice, but mice lacking the IL-12 p40 subunit show progressive growth of the parasite
Fig. 11.18 Continuous IL-12 is necessary for resistance to pathogens requiring TH1 responses. Mice that have eliminated an infection with Leishmania major and have generated TH1 cells specific to the pathogen were used as a source of T cells that were adoptively transferred either into Rag2-deficient mice, which lack T cells and B cells and cannot control L. major infection but can produce IL-12, or into mice lacking IL-12 p40, which cannot produce IL-12. On subsequent infection of the Rag2-deficient mice, lesions did not enlarge because the transferred TH1 cells conferred immunity. But despite the fact that the transferred cells were already differentiated TH1 cells, they did not confer resistance to IL-12 p40-deficient mice, which lacked a source of IL-12 to support TH1 function.
Fig. 11.19 Effector T cells can be activated to release cytokines independently of antigen recognition.
Analogous to ILCs, effector T cells can be stimulated to produce effector cytokines independently of T-cell receptor signaling via the coordinate actions of pairs of cytokines.
which activates type 2 responses, is inactivated by the inflammasome, indicating another basis for counterregulation between type 2 and type 1 or type 3 immune responses. Although the precise role of noncognate activation of effector T cells by cytokines is not clearly defined, it may provide a mechanism by which tissue-resident memory T cells could be rapidly recruited in recall, or memory, responses (see Section 11-22).
11-13 Effector T cells demonstrate plasticity and cooperativity that enable adaptation during anti-pathogen responses.