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Thymic stromal lymphopoietin (TSLP) acts on dendritic cells (DCs), which prime helper T (Th) cells to become type 2 cytokine producing cells. Recently, a different set of populations of TSLP-responsive DCs has been discovered. Here, we identified two populations of CD103 lo EpCAM hi migratory DCs (fraction I and fraction II) that accumulated in skin-draining lymph nodes in response to TSLP expressed in the mouse skin. Fraction I DCs with CD11b + PDL2 hi expression primed naïve Th cells to differentiate into cells secreting IFN-γ, IL-17A and IL-22, while fraction II DCs with CD11b lo PDL2 + expression primed naïve Th cells to differentiate into cells secreting IL-4, IL-5, IL-9, IL-13 and IL-10. Fraction I DCs migrated from the skin via IL-4Rα signaling pathway, whereas fraction II DCs migrated partially via TSLPR signaling pathway. All suggest that at least two populations of CD103 lo EpCAM hi DCs with distinct functions and pathways could migrate in response to TSLP expression in the skin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

T helper type 2 (Th2) cytokines, IL-4 and IL-13, attenuate the expression of genes that regulate epidermal cellular structures and the barrier function at the terminal stage of keratinocyte differentiation. However, whether these Th2 cytokines act at earlier stages remains unknown. We investigated the roles of cytokines in expression levels of mRNAs and/or proteins in primary mouse keratinocytes and human keratinocyte HaCaT cells at earlier stages. We showed that IL-4 downregulated the expression levels of Krt1, Krt10, Dsg1, and Dsc1 via IL-4Rα- and signal transducer and activator of transcription factor 6 (STAT6)-dependent mechanisms in differentiating mouse keratinocytes at early stages. As the expression levels of keratin-1 and -10 in the keratinocytes transiently expressing an active form of STAT6 were not downregulated, STAT6 and other IL-4-induced molecules may synergistically regulate this expression. The restoration of the downregulated expression levels of Krt1 and Krt10 induced by IL-4 with the MEK (mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase) inhibitor U0126 indicated the involvement of the p44/42 MAPK signaling pathway in the attenuated expression. IL-13 also downregulated the expression of the four genes. Furthermore, IL-4 or IL-13 caused the downregulation of these genes in HaCaT cells and promoted the fragmentation of cell sheets with mechanical stress. Our results showed that IL-4 or IL-13 acted on differentiating keratinocytes in vitro at early stages to attenuate the gene expression.

Background: Inducible co-stimulator (ICOS) is a co-stimulatory receptor on activated T cells that provides the signals needed for Th1 and Th2 responses via its interaction with B7h. Chronic focal infections are closely related to pustulosis palmaris et plantaris (PPP), but the involvement of ICOS in PPP has not been clarified., Objective: To investigate the effectiveness of treatments for focal infections on PPP skin lesions and the involvement of ICOS-positive T cells at focal infection sites in the tonsils and in PPP lesional skin., Methods: In patients that had undergone a tonsillectomy or dental treatment, the clinical activities of PPP, both the skin lesions and pustulotic arthro-osteitis were followed for over 2 years. The expressions of ICOS and various other activation markers on T cells were examined in tonsil tissue from both PPP patients and non-PPP patients, and the expression levels in peripheral blood were also evaluated in PPP patients and healthy donors. ICOS-positive T cells and B7h expression in PPP and normal skin were examined immunohistochemically., Results: The above treatments for focal infections led to a dramatic and persistent improvement in the PPP skin lesions and pustulotic arthro-osteitis. The expression of ICOS, but not of other activation markers, was higher in tonsil tissues from PPP patients than in tonsil tissues from non-PPP patients. B7h was upregulated without numerous ICOS-positive T cell infiltrates in the skin lesions., Conclusion: The activation of T cells via ICOS co-stimulation in focal infections likely triggers the skin and skeletal inflammation associated with PPP, resulting in tissue damage.

The long-term exposure of mice to superantigen SEA using a mini-osmotic pump (SEA pump) induced a long-lasting expansion of Vbeta3+ CD4+ T cells with T helper (Th) 2 cell-type properties. Removal of the SEA pump 10 days after pump implantation did not significantly alter the level of Vbeta3+ CD4+ T cell expansion/maintenance. Furthermore, CFSE-labeled CD4+ T cells failed to divide when transferred to post-implantation day 15 mice. Thus, CD4+ T cells appeared to survive for at least 30 days in the absence of a sufficient amount of antigen to trigger cell division. STAT6 deficient mice, in which Th2 cell development is largely impaired, also exhibited a protracted cell expansion, similar to that observed in normal mice, suggesting that the Th2 cell property is dispensable for the maintenance of Vbeta3+ CD4+ T cell expansion. The expanded CD4+ T cells on post-implantation day 26 were arrested in the G0/G1 phase of the cell cycle and showed a lower level of cell division upon restimulation. The Cdk inhibitor p27(Kip1) was highly expressed, and Cdk2 was downregulated. Moreover, the CD4+ T cells were resistant to in vitro apoptosis induction in parallel with their level of Bcl-2 expression. Collectively, the Vbeta3+ CD4+ T cells appeared to develop into long-lived memory T cells with cell cycle arrest upon long-term exposure to SEA.

We previously reported that Vbeta3+ CD4+ T cells maintained a protracted expansion, with the phenotypes of memory Th2 cells, for 30 days in C57BL/6 (B6) mice implanted with SEA-containing mini-osmotic pumps. In the present study, we followed the fate of Vbeta3+ CD4+ T cells in CD28-/- mice. Vbeta3+ CD4+ T cells increased to a degree similar to that of B6 Vbeta3+ CD4+ T cells until day 10 after implantation, then declined rapidly reaching the control level by 28 days. Remaining Vbeta3+ CD4+ T cells at that time did not exhibit memory phenotypes nor Th2-deviated responses. The rapid drop in Vbeta3+ CD4+ T cells in CD28-/- mice was attributable to upregulated induction of apoptosis owing to marginal inductions of Bcl-2 and Bcl-xL. Collectively, these data indicate CD28 to play critical roles in the generation and maintenance of SEA-reactive CD4+ T cells in vivo.