Given the importance of cytokines in T cell development and differentiation and function, it is no surprise that Stat proteins contribute critically to each of these processes (). As an example of the overall importance of cytokine-cytokine receptor-Jak-Stat pathway signaling in thymic T cell development, IL-7 signaling ensures development of appropriate lymphocyte numbers. Mutation of either IL-7R subunit, IL-7Ra or γc (encoded by IL2RG
) or its cognate Jak, JAK3, lead to SCID manifested by severely reduced numbers of thymocytes (O’Shea et al., 2004a
). IL-7 activates Stat5a and Stat5b and deletion of the locus encoding Stat5a and Stat5b also results in a severe SCID phenotype (Yao et al., 2006
). Indeed, Stat5 activity is required for the normal development of all normal lymphoid lineages. However, the absolute role of Stat5 in permitting normal T cell development is only part of Stat5’s contribution to T cell subset development discussed below.
Cytokine signaling in T cell development and function
T cells were thought to have two fates – T helper1 (Th1) and Th2 cells. These fates are driven by the cytokine milieu with IL-12 driving Th1 differentiation and IL-4 promoting Th2 differentiation. IL-12 activates Stat4 whereas IL-4 activates Stat6. Stat4- and Stat6-deficient mice have impaired Th1 and Th2 responses respectively (O’Garra and Arai, 2000
). The products of Th1 and Th2 T cells, IFN-γ and IL-4 respectively, promote commitment to their respective lineages and inhibit development of the opposing lineage. Surprisingly, a recent genome-wide association study has revealed that polymorphisms in STAT4
confer risk of developing autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (Remmers et al., 2007
). While RA has typically been view as having elements consistent with Th1-mediated pathology, SLE would not be considered prototypic Th1 disease. In this regard, it is important to note that Type I IFNs also activate Stat4. Depending upon the circumstance, Type I IFN signaling may enhance or inhibit Th1 responses (Nguyen et al., 2002
). Although the pathogenesis of SLE is very poorly understood, recent advances have documented that SLE and related autoimmune disorders are characterized by a transcriptional “interferon signature”. Exactly how Stat4 and IFNs contribute to the pathogenesis of SLE is unknown, but this will be an important area to follow.
As important as the Th1-Th2 paradigm was in advancing our understanding of T cell biology, CD4+
T cells are now known to have additional fates regulated by Stat3 and Stat5. One subset of CD4+
T cells is termed regulatory T (Treg) cells, which express the transcription factor Foxp3 (). Treg cells are discussed in detail in a review in this issue by Rudensky. Tregs have essential immunosuppressive functions as illustrated by the fact that deletion or mutation of Foxp3
leads to fatal autoimmune disease in mice and humans. CD4+
Treg cells can be generated in the thymus (‘natural’ Tregs) or can be induced in the periphery (iTregs). In both cases, cytokines that use γc are important drivers of Treg development. Deficiency of γc or Jak3 cause a failure to produce Foxp3-positive regulatory T cells (Mayack and Berg, 2006
). Accordingly, deficiency of both Stat5a and Stat5b also leads to loss of Tregs and inability to induce Tregs in vitro (Yao et al., 2007
) while constitutive activation of Stat5b enforces Foxp3-positive Treg development, bypassing the requirements for upstream cytokine or co-stimulatory signals (Burchill et al., 2008
). Stat5 appears to have very direct effects on Tregs in that these transcription factors bind directly to the Foxp3
gene. Thus, even though Stat5 is absolutely required for T cell development, once T cells have developed and exited the thymus, further Stat5-dependent signals are needed to ensure correct subset development and function. One way to think about the requirement for Stat5 to have such diverse functions in T cell development is to consider that cytokine signaling via Stat5, and gene accessibility to Stat5, is partitioned throughout the life of the T cell: while IL-7/Jak3/Stat5 signaling is predominant for thymic development, other Stat5-activating receptors stimulate T cells and activate different combinations of Stat5-dependent genes following maturation and exit from the thymus.
Another recently recognized fate for CD4+
T cells is the Th17 cell (also discussed by the other reviews in this issue) whose development and function is critically dependent on Stat3. Named for their ability to produce the inflammatory cytokine IL-17, Th17 cells recruit and activate neutrophils and other inflammatory cells to sites of tissue inflammation (Korn et al., 2007
). Th17 cells can be generated from naïve CD4+
T cells by IL-6 and TGFβ, but also produce another cytokine IL-21, which promotes IL-17 production in an autocrine-paracrine manner (Nurieva et al., 2007
; Zhou et al., 2007
). Finally, a third cytokine, IL-23, acts on memory cells to expand and maintain Th17 cells. The importance of IL-23 signaling in inflammation is exemplified by recent discoveries that polymorphisms in IL23R
are associated with increased risk of inflammatory bowel disease, ankylosing spondylitis and psoriasis (Burton et al., 2007
; Cargill et al., 2007
; Duerr et al., 2006
; Tremelling et al., 2007
IL-6, IL-21 and IL-23 all activate Stat3 via their cognate receptors (). Accordingly, selective deletion of Stat3 in T cells abrogates Th17 differentiation in part because the expression of RORγt and RORα, two nuclear hormone receptors essential for Th17 development, is also abrogated (Yang et al., 2008
). However, Stat3 also directly regulates the expression of Il21
(Chen et al., 2006
; Wei et al., 2007
). Therefore Th17 fate, peripheral maintenance by IL-21, and effector functions are all regulated by Stat3 signaling from different cytokine receptors. The importance of Stat3 in Th17 development and function is exemplified by the fact that patients with Job’s syndrome, an autosomal dominant disorder due to Stat3 mutations, fail to make Th17 cells (Milner et al., 2008
). Parenthetically, it is interesting to note that IL-2 acting through Stat5 inhibits Th17 differentiation (Laurence et al., 2007
). Thus, the balance of Treg/Th17 differentiation appears to be regulated by Stat5 and Stat3. Clearly the use of one transcription factor to perform all these functions indicates that Stat3 activity is under tight control throughout the life of a Th17 cell, a task performed in part by Socs3 (discussed below).
An additional complexity of Th17 T cells in inflammation concerns the Stat3-activating cytokine IL-22 (IL-22 signaling is discussed below). Th17 cells preferentially produce IL-22, but its regulation is subtly different from IL-17; whereas IL-6 and TGFβ-1 are important for the differentiation of Th17 cells, IL-6 alone so far appears to be capable of inducing IL-22. The pathways for generating IL-22 are discussed in accompanying reviews in this issue. However, Th17 cells are not the only cell capable of producing IL-22 and the extent to which this cytokine expression is dependent upon which Stat proteins remains to be determined. Perhaps more important are the upstream cytokine signals that drive IL-22 production from Th17 cells at sites of tissue inflammation.
In summary, even though Stat5 is absolutely required for normal T cell development, once T cells have developed and exited the thymus, further Stat5 and Stat3 signals are needed to ensure correct subset development and function. Stats have direct and essential roles in helper T cell development, lineage commitment and function as they bind and presumably regulate genes such as Foxp3, Il17a and Il21. The actions of these Stats may be direct or indirect, but clearly warrant further investigation in defining direct Stat targets in T cells and the mechanisms by which the induce transcriptional programs.