Thus far we have discussed subsets of effector CD4 T cells as though they are intrinsically stable, such that their functional phenotype is unchanging after their development. Similarly, we have discussed the different types of immunity as though they are unimodal, that is, only one type of response is recruited to clear a given pathogen. Although this is often the case, it is not always so. Just as the pathogens can modify their tactics to evade destruction, so too can the elicited effector T cells adapt in order to clear the host of these pathogens. Adaptation can occur by flexibility in the programming of individual T cells, referred to as T-cell plasticity, wherein effector T cells can transition into different cytokine phenotypes contingent on changes in the local inflammatory environment. It can also occur as a result of cooperation between different subsets of T cells. Plasticity applies to cells of the same clonal origin and identical antigenic specificity, whereas cooperation applies to cells that develop from different clonal precursors and target different antigens, typically at different stages of an infection.
Although some degree of plasticity has been experimentally demonstrated for each of the major effector CD4 subsets, it appears to be most prevalent in type 3 responses. It is common for TH17 cells to deviate, or be ‘reprogrammed,’ into TH1-type cells (Fig. 11.20). This was originally discovered using cytokine reporter mice, in which TH17 cells that express IL-17F could be identified and isolated based on their expression of a cell-associated reporter molecule controlled by the Il17f gene. When TH17 cells isolated using the reporter were restimulated in the presence of the TH1-polarizing cytokine IL-12, their progeny rapidly lost expression of IL-17 and acquired expression of IFN-γ. Moreover, repetitive restimulation of TH17 cells with the TH17 lineage cytokine IL-23 could lead to a subset of progeny that also acquired features of TH1 cells. In both cases, reprogramming of TH17 cells into TH1 cells required expression of the TH1-associated transcription factor T-bet and loss of the TH17-associated transcription factor RORγt, both of which were contingent on activation of STAT4 by the IL-12 and IL-23 receptors. Thus, TH17 cells deficient for either T-bet or STAT4 failed to demonstrate transition into TH1 cells, or ‘TH17 cell plasticity.’