CD4(+) T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (T(H)1) or T(H)2 lineages and instead favor the idea of a distinct effector lineage we call 'T(H)-17'. The development of T(H)-17 cells from naive precursor cells was potently inhibited by interferon-gamma (IFN-gamma) and IL-4, whereas committed T(H)-17 cells were resistant to suppression by T(H)1 or T(H)2 cytokines. In the absence of IFN-gamma and IL-4, IL-23 induced naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6. These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity.

Trent and colleagues, in their original study of heart failure in patients receiving imatinib, discuss the retrospective nature of similar studies and the difficulty of attributing symptoms of heart failure to the drug. 1 The symptoms of heart failure, including edema and pleural effusion, can also result from T-cell abnormalities with the tyrosine kinase inhibitors. Peripheral edema can arise from a T-helper-1 (Th1) cell-mediated hypersensitive reaction, whereas pleural effusions and pulmonary involvement are known to be T-cell-mediated. 2 In support of the latter, a series of 40 patients on dasatinib yielded 6 individuals who developed pleural effusions and lung involvement with lymphocytic infiltration, rather than cardiac impairment. 3 If edema and pulmonary involvement develop secondary to T-cell abnormalities, withholding the drug until symptoms resolve, followed by gradual reintroduction at lower doses, is preferable to attributing these adverse effects to ''drug-induced cardiac toxicity''. 3 The importance of imatinib to T-cell responses has been studied. However, its effects on the balance between the Th1 and Th2 clones are likely as important. 4 Although the cytokines elaborated by either of these clones can serve as autocrine growth factors, they also regulate the development and differentiation of each other. 5 For this reason, edema or pleural effusion in certain individuals may be explained by the balance of Th1 to Th2 suppression by imatinib. Relative excess of the former causes adverse effects, whereas the latter can be beneficial in autoimmune disorders. Individuals with autoimmune disorders with a higher Th2:Th1 ratio are suitable candidates for imatinib for similar reasons. Thus, it is important to dissect the adverse effects of imatinib into those related to T-cell and heart abnormalities , so that an effective drug is not withheld. REFERENCES 1. Trent JC, Patel SS, Zhang J, et al. Rare incidence of conges-tive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate. Cancer. 2010; 116:184-192. 2. Li L, Elliott JF, Mosmann TR. IL-10 inhibits cytokine production , vascular leakage, and swelling during T-helper-1 cell-induced delayed-type hypersensitivity. J Immunol. 1994;153: 3967-3978. 3. Bergeron A, Réa D, Levy V, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia. Am J Respir CritCareMed. 2007;176:814-818. 4. Seggewiss R, Price DA, Purbhoo MA. Immunomodulatory effects of imatinib and second generation tyrosine kinase inhibitors on T cells and dendritic cells. Concerning our recent article, 1 the comments by Dr. Jecko are thought-provoking and well-received. Dr. Jecko poignantly and rationally postulates a mechanism by which tyrosine kinase inhibitors modulate T-cell function , resulting in pleural effusions and edema. Imatinib-associated edema and pleural effusions are a common detriment to patient quality of life, and the pathophysiology remains unknown. Therefore, rigorous evaluation of alternate potential mechani...

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While in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α + dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. Here we show that deletion of the transcription factor Batf3 ablated development of CD8α + dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3 -/-mice were defective in cross-presentation and Batf3 -/-mice lacked virusspecific CD8 + T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3 -/-mice. These results suggest an important role for CD8α + dendritic cells and cross-presentation in responses to viruses and in tumor rejection.During antigen 'cross-presentation' (1), antigens generated in one cell are presented by MHC class I molecules of a second cell. It remains unclear whether all antigen presenting cells (APCs) use cross-presentation and whether this pathway plays a role in immune responses in vivo (2). Dendritic cells (DCs) are a heterogeneous group of APCs with two major subsets, plasmacytoid dendritic cells (pDCs) and conventional CD11c + dendritic cells (cDCs) (3). Subsets of cDCs include CD8α + , CD4 + , and CD8α -CD4 -populations that may exert distinct functions in immune responses. Evidence has suggested that CD8α + cDCs are important for cross-presentation during infections, but is based on ex vivo analysis (4-6) or in vitro antigen loading (7). Evidence both for and against a role for cross-presentation in responses against tumors has been reported (8-10).Attempts have been made to study the in vivo role of dendritic cells by selective depletion. Diphtheria toxin treatment can deplete all CD11c hi cells in one transgenic mouse model (11), but affects splenic macrophages and activated CD8 + T cells (12). Gene targeting of transcription factors (e.g., Irf2, Irf4, Irf8, Stat3 and Id2) has caused broad defects in several DC subsets, T cells and macrophages (13). To identify genes regulating DC development, we performed global gene expression analysis across many tissues and immune cells ( fig S1A). Batf3 (p21SNFT) (14) was highly expressed in cDCs, with low to absent expression in other *To whom correspondence should be addressed. E-mail murphy@pathology.wustl.edu. fig. S1B-D).In spleens of Batf3 -/-mice we found a selective loss of CD8α + cDCs, without abnormalities in other hematopoietic cell types or architecture (Fig. 1, fig. S2-S11). CD8α + cDC coexpress DEC205, CD24, and low levels of CD11b (3,15). Batf3 -/-mice lacked splenic CD11c hi CD8α + DEC205 + cells (Fig. 1A), showed a loss of CD11c hi CD11b dull cells and CD11c hi CD8α + CD24 + cells (Fig. 1B), but had normal populations of CD4 + and CD8α -CD4 -cDC subsets (Fig. 1B). Lymph nodes and thymi of Batf3 -/-mice lacked CD8α + DCs but had normal distributions of CD8α -CD11c + cells (Fig. 1C). DEC205 int and DEC205 hi DCs were present in lymph nodes draining the skin of Batf3 -/-mice (Fig. 1C), and show...