Cutting Edge: Differential Expression of Chemokines in Th1 and Th2 Cells Is Dependent on Stat6 But Not Stat4

Polarization of the immune response toward a type 1 cytokine profile has been posited to be associated with a therapeutic antitumor immune response. STAT6−/− mice are unable to generate a type 2 immune response, and instead mount an enhanced type 1 response. STAT6−/− mice are significantly more resistant to 4T1, a mammary adenocarinoma cell line, resisting a 10-fold higher tumor dose compared with wild-type (wt) BALB/c mice. An analysis of the T cells from tumor-bearing STAT6−/− mice revealed that they contained a population primed by a peptide (STAT6531–539) of the STAT6 protein expressed in 4T1. The adoptive transfer of T cells from STAT6531–539-vaccinated STAT6−/− mice significantly reduced the number of 4T1 pulmonary metastases in recipient mice. Additionally, the role of these STAT6531–539-reactive T cells against s.c. 4T1 tumor challenge was determined by tumor-challenging wt BALB/c mice reconstituted with STAT6−/− bone marrow, thereby assessing whether a polarized type 1 immune response in the absence of STAT6-reactive T cells was sufficient to reject a 4T1 tumor challenge. T cells from the STAT6−/− bone marrow chimeras failed to recognize the STAT6531–539, and these mice proved to be as susceptible as wt BALB/c mice to 4T1 challenge. This demonstrated that the absence of STAT6531–539-reactive T cells correlated with the inability to reject 4T1 challenge. Additionally, these data emphasize that the enhanced ability to mount a type 1-polarized immune response is inconsequential if a sufficient antitumor immune response is not primed by the tumor.

Section: Peptide-specific T Cells From Bm Chimeras Fail To Reject 4t1mentioning

confidence: 67%

Regression of a Mammary Adenocarcinoma in STAT6−/− Mice Is Dependent on the Presence of STAT6-Reactive T Cells

Jensen

Meijer²,

Kurt

et al. 2003

“…T he chemokines thymus-and activation-regulated chemokine/CC chemokine ligand 17 (CCL17) 3 and macrophage-derived chemokine (MDC/CCL22) can be classified as both homeostatic and inflammatory chemokines and exert their effects via the chemokine receptor CCR4. CCR4 is expressed on Th2 cells (1)(2)(3)(4), CLA ϩ cutaneous memory T cells (5), NK cells (6), thymocytes (7,8), immature dendritic cells, basophils, and platelets (9,10).…”

mentioning

confidence: 99%

“…CCR4 is expressed on Th2 cells (1)(2)(3)(4), CLA ϩ cutaneous memory T cells (5), NK cells (6), thymocytes (7,8), immature dendritic cells, basophils, and platelets (9,10). Due to the fact that CCR4 was initially thought to be exclusively expressed on Th2 cells, early pathological roles for CCR4 concentrated on known Th2-mediated conditions.…”

mentioning

confidence: 99%

“…Several recent studies have highlighted that the activation of class 1 PI3K and subsequent PI(3,4,5)P 3 generation is a crucial event in the detection of a chemoattractant gradient (33)(34)(35)(36). PI3K␥ (a class I B PI3K) is the only G␤␥-dependent PI3K, and the central role it plays in chemokinemediated PI (3,4,5)P 3 accumulation is demonstrated in PI3K␥ neutrophils and subsequent migration (37)(38)(39)(40). However, loss of PI3K␥ activity does not lead to complete abolition of the directional motility of all cells, and its requirement for migration may be restricted to the myeloid lineage (39).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activation of Phosphoinositide 3-Kinases by the CCR4 Ligand Macrophage-Derived Chemokine Is a Dispensable Signal for T Lymphocyte Chemotaxis

Cronshaw

Owen

Brown

et al. 2004

Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its cellular effects principally by binding to its receptor CCR4, and together they constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles in the body. We report the CCL22-induced accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3) in the leukemic T cell line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM cells in a pertussis toxin-sensitive manner. Although the PI(3,4,5)P3 accumulation along with the pertussis toxin-susceptible phosphorylation of protein kinase B were sensitive to the two phosphoinositide 3-kinase inhibitors, LY294002 and wortmannin, cell migration was unaffected. However, cell migration was abrogated with the Rho-dependent kinase inhibitor, Y-27632. These data demonstrate that although there is PI(3,4,5)P3 accumulation downstream of CCR4, phosphoinositide 3-kinase activity is a dispensable signal for CCR4-stimulated chemotaxis of Th2 cells and the CEM T cell line.

“…First, the source of XCL1 within the immune system is still poorly defined. On the one hand, lymphotactin synthesis was originally described as strictly confined to CD8 ϩ T cells (8 -12); more recently, XCL1 expression was also reported in several other leukocyte populations, including NK cells (7,13,14), dendritic cells (15), activated mast cells (16), TCR ␥␦ ϩ T cells (17,18), and even CD4 ϩ T cells (19), especially those belonging to the Th1 subset (20,21). In most cases, however, no quantitative comparisons between different cell populations were performed, and the ability to produce XCL1 was mostly evaluated by nonquantitative PCR approaches.…”

mentioning

confidence: 99%

CD8+αβ+ T Cells That Lack Surface CD5 Antigen Expression Are a Major Lymphotactin (XCL1) Source in Peripheral Blood Lymphocytes

Stievano

Tosello

Marcato

et al. 2003

To better characterize the cellular source of lymphotactin (XCL1), we compared XCL1 expression in different lymphocyte subsets by real-time PCR. XCL1 was constitutively expressed in both PBMC and CD4+ cells, but its expression was almost 2 log higher in CD8+ cells. In vitro activation was associated with a substantial increase in XCL1 expression in both PBMC and CD8+ cells, but not in CD4+ lymphocytes. The preferential expression of XCL1 in CD8+ cells was confirmed by measuring XCL1 production in culture supernatants, and a good correlation was found between figures obtained by real-time PCR and XCL1 contents. XCL1 expression was mostly confined to a CD3+CD8+ subset not expressing CD5, where XCL1 expression equaled that shown by γδ+ T cells. Compared with the CD5+ counterpart, CD3+CD8+CD5− cells, which did not express CD5 following in vitro activation, showed preferential expression of the αα form of CD8 and a lower expression of molecules associated with a noncommitted/naive phenotype, such as CD62L. CD3+CD8+CD5− cells also expressed higher levels of the XCL1 receptor; in addition, although not differing from CD3+CD8+CD5+ cells in terms of the expression of most α- and β-chemokines, they showed higher expression of CCL3/macrophage inflammatory protein-1α. These data show that TCR αβ-expressing lymphocytes that lack CD5 expression are a major XCL1 source, and that the contribution to its synthesis by different TCR αβ-expressing T cell subsets, namely CD4+ lymphocytes, is negligible. In addition, they point to the CD3+CD8+CD5− population as a particular T cell subset within the CD8+ compartment, whose functional properties deserve further attention.