Accumulation of Effector CD4 T Cells during Type 2 Immune Responses Is Negatively Regulated by Stat6

Abstract

Th2 cells are important effector cells during allergic disorders and parasite infections. Efficient differentiation of Th2 cells requires signaling via the IL-4R and the transcription factor Stat6. Stat6 is further implicated in Th2 cell recruitment to the lung and might be required for the survival of memory Th2 cells. We analyzed the role of Stat6 in T cell expansion, survival, and recruitment to the lung using competitive adoptive transfer experiments and infection with the helminth parasite Nippostrongylus brasiliensis. Stat6 was not required in T cells or other cell types for recruitment of in vivo-generated Th2 cells to the lung. Functional analysis of Th2 memory cells revealed that Stat6 signaling in CD4 T cells was dispensable for memory cell generation, expansion, and cytokine secretion. However, Stat6-deficient T cells survived better than wild-type T cells, resulting in higher accumulation in the bronchoalveolar lavage, lung, and lymph nodes. This demonstrates that effector T cell expansion is negatively controlled by a novel Stat6-dependent mechanism which probably serves to limit the number of effector T cells during the acute phase of the immune response and thereby lowers the risk of bystander toxicity against healthy tissues.

The Lung Is an Important Site for Priming CD4 T-Cell-Mediated Protective Immunity against Gastrointestinal Helminth Parasites

“…A recent paper by King et al (15) suggests that STAT6 Ϫ/Ϫ animals have unimpaired memory Th2 responses, retaining proliferative capacity and function, as well as showing enhanced recruitment to the lung. This confirms our finding that simply mounting a Th2 response is not enough to protect from reinfection.…”

Hookworm virulence factors: making the most of the host

“…Eosinophils seem to contribute to immunity during secondary infection and AAMs protect against primary infection with N. brasiliensis and secondary infection with H. polygyrus [76]. Stat6 is not required for T cell recruitment to effector sites or for generation of memory T cells during H. polygyrus [100] or N. brasiliensis infection [99], although it plays a role in limiting effector T cell numbers both in primary and secondary immune responses to H. polygyrus infection [100].…”

“…The IL-4/Stat6 signaling pathway can also cause apoptosis in T cells in order to control the accumulation of Th2 cells in tissues which could cause severe side effects to healthy tissue. Nonetheless, Stat6 is not required for the initial differentiation of IL-4 producing T cells, whereas secondary responses to the same pathogen are Stat6 dependent [100].…”

Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2

“…2 Th2 cells require Stat6 to maintain their differentiation state, although initial commitment is Stat6-independent. 3,4 Stat6 regulates class switch recombination to IgE in B cells and expression of chemokines like Ccl11, Ccl17, Ccl22, and Ccl24, which mediate recruitment of eosinophils and other effector cells to target tissues. 1 Stat6 further induces goblet cell hyperplasia, collagen production by fibroblasts, activates smooth muscle cells, and is required for expulsion of gastrointestinal helminths.…”

“…1 IL-4R␣ can also trigger Stat6-independent signaling pathways leading to activation of the mitogen-activated protein kinase (MAPK) or phosphoinositide-3 kinase (PI3K) pathways that can enhance cell growth and survival. 2 Th2 cells require Stat6 to maintain their differentiation state, although initial commitment is 4 Stat6 regulates class switch recombination to IgE in B cells and expression of chemokines like Ccl11, Ccl17, Ccl22, and Ccl24, which mediate recruitment of eosinophils and other effector cells to target tissues. 1 Stat6 further induces goblet cell hyperplasia, collagen production by fibroblasts, activates smooth muscle cells, and is required for expulsion of gastrointestinal helminths.…”