IL-4 Attenuates Th1-Associated Chemokine Expression and Th1 Trafficking to Inflamed Tissues and Limits Pathogen Clearance

Abstract

Interleukin 4 (IL-4) plays a central role in the orchestration of Type 2 immunity. During T cell activation in the lymph node, IL-4 promotes Th2 differentiation and inhibits Th1 generation. In the inflamed tissue, IL-4 signals promote innate and adaptive Type-2 immune recruitment and effector function, positively amplifying the local Th2 response. In this study, we identify an additional negative regulatory role for IL-4 in limiting the recruitment of Th1 cells to inflamed tissues. To test IL-4 effects on inflammation subsequent to Th2 differentiation, we transiently blocked IL-4 during ongoing dermal inflammation (using anti-IL-4 mAb) and analyzed changes in gene expression. Neutralization of IL-4 led to the upregulation of a number of genes linked to Th1 trafficking, including CXCR3 chemokines, CCL5 and CCR5 and an associated increase in IFNγ, Tbet and TNFα genes. These gene expression changes correlated with increased numbers of IFNγ-producing CD4+ T cells in the inflamed dermis. Moreover, using an adoptive transfer approach to directly test the role of IL-4 in T cell trafficking to the inflamed tissues, we found IL-4 neutralization led to an early increase in Th1 cell recruitment to the inflamed dermis. These data support a model whereby IL-4 dampens Th1-chemokines at the site of inflammation limiting Th1 recruitment. To determine biological significance, we infected mice with Leishmania major, as pathogen clearance is highly dependent on IFNγ-producing CD4+ T cells at the infection site. Short-term IL-4 blockade in established L. major infection led to a significant increase in the number of IFNγ-producing CD4+ T cells in the infected ear dermis, with no change in the draining LN. Increased lymphocyte influx into the infected tissue correlated with a significant decrease in parasite number. Thus, independent of IL-4's role in the generation of immune effectors, IL-4 attenuates lymphocyte recruitment to the inflamed/infected dermis and limits pathogen clearance.

Cutaneous, Purpuric Painful Nodules Upon Addition of Ibrutinib to RCVP Therapy in a CLL Patient: A Distinctive Reaction Pattern Reflecting Iatrogenic Th2 to Th1 Milieu Reversal

“…Furthermore, IL-4 and IL-13 suppress Th1 immunity by inhibiting production of Th1 cytokines like IFNg and by inhibiting the production of Th1 effectors themselves. 33,34 Thus, the absence of IL-4 and IL-13 unfetters the Th1 response. A more obvious contributor to the IgE deficit than ibrutinib's action on mast cells and basophils is ibrutinib's destruction of B-lymphocytes.…”

Commentary: IL-4 and IL-13 receptors and signaling

“…To date, very few therapeutic approaches have been effective in regulating IL-17 responses. Since IL-4 is known to be a potent negative regulator of CD4+ Th1/Th17 (134) and IL-17-producing γδ, a therapeutic IL-4 superkine may be an effective way to dampen unchecked Th1/17-driven inflammation in autoimmune diseases and asthma. Since human T and B cells predominantly express γC and not IL-13Rα1, a superkine that specifically binds γC to enhance the Th2-differentiation program, without influencing non-structural cells expressing the IL-13Rα1, may be an effective way to modulate inappropriate inflammation.…”

Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming

“…Furthermore, there are reports that IL-4 programming of M2 macrophages may be a detriment towards macrophage-derived bacterial clearance (29). Therefore, we tested whether IL-4 would be beneficial in , and Ym1 quantified in the whole lung at days 4 and 6 among intratracheal H2O-or LPS-exposed mice with IL-4 or PBS treatment (n ϭ 3-6, *P Ͻ 0.05, **P Ͻ 0.01, and ***P Ͻ 0.001 by one-way ANOVA).…”