Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

Abstract

We have previously shown that regulatory T (Treg) cells that accumulate in the airways of allergic mice upregulate CC-chemokine receptor 4 (CCR4) expression. These Treg cells suppressed in vitro Th2 cell proliferation but not type 2 cytokine production. In the current study, using a well-established murine model of allergic lung disease or oral tolerance, we evaluated the in vivo activity of Treg cells in allergic airway inflammation with special focus on CCR4 function. We found that allergic, but not tolerant, mice treated with anti-CD25 Ab showed increased airway eosinophilia and IL-5– or IL-4–producing Th2 cells when compared with untreated mice. Notably, mice with CCR4 deficiency displayed an augmented airway allergic inflammation compared with wild-type or CCR2 knockout (KO) mice. The allergic phenotype of CCR4KO mice was similar to that observed in anti-CD25–treated mice. The exacerbated allergic inflammation of CCR4KO mice was directly associated with an impaired migration of Treg cells to airways and augmented frequency of pulmonary Th2 cells. Adoptive transfer of CD25+CD4+ T cells expressing high levels of CCR4, but not CCR4KO CD25+CD4+ T cells, attenuated the severe airway Th2 response of CCR4KO mice. Our results show that CCR4 is critically involved in the migration of Treg cells to allergic lungs that, in turn, attenuate airway Th2 activation and allergic eosinophilic inflammation.

Itch expression by Treg cells controls Th2 inflammatory responses

“…*P < 0.05; **P < 0.01; ***P < 0.001. (38). However, other possible mechanisms, such as para-activated CD4 + T cells or other inflammatory cells, require further investigation.…”

Genetic Deletion of β-Arrestin-2 and the Mitigation of Established Airway Hyperresponsiveness in a Murine Asthma Model

“…One possible explanation for the persistence of inflammation is that insufficient time elapsed between barr2 gene deletion and assessment of inflammation. The mitigation of airway inflammation in murine models is associated with migration of regulatory T cells to airways (29) and egress of effector T cells from lung to lymph nodes, processes that may take weeks after allergen challenge ends (1,30,31). The unanticipated delay in, and the incompleteness of, barr2 deletion may have been a result of interference by OVA-induced stimulation of barr2 transcription versus tamoxifeninduced Cre-mediated recombination of the barr2 gene because it is highly unlikely that existing barr2 protein could persist in live cells for 3 weeks.…”

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…DOCK8-deficient Tregs demonstrated decreased expression of several IL-2-regulated genes that included Foxp3 and Il2ra, consistent with impaired IL-2-driven STAT5 phosphorylation. There was also decreased expression of several transcription factors that affect Treg stability and subset development (62,67,68,72,74,82,83). This may be relevant to the rampant Th1/Th17 intestinal inflammation observed in mice.…”