CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes

Abstract

CD4+ Th2 cells are important regulators of allergic inflammation. CCR8 is thought to play a role in Th2-mediated responses, however, expression of CCR8 in peripheral blood has not been fully characterized. Using a fluorescent form of the ligand selective for CCR8 (F-CCL1), we identified the leukocytes expressing CCR8 in human, monkey, and mouse peripheral blood. CCR8 expression is primarily restricted to a subset of human CD4 memory T lymphocytes (15%). Approximately 40% of CCR8+CD4+ T cells express Th2 cytokines IL-4 or IL-13 while 13% express the Th1 cytokine IFN-γ. In fact, 50% of all Th2, but only 5% of Th1, cells express CCR8. Upon anti-CD3/anti-CD28 mAb-mediated activation, CCR8+CD4+ T cells secrete 3- to 7-fold higher levels of IL-4, IL-5, IL-9, and IL-13 and 10- to 20-fold lower levels of IFN-γ or IL-17, compared with CCR8−CD4+ memory T cells. Two-thirds of CCR8+CD4 T cells express cutaneous lymphocyte-associated Ag while the majority lack gut-homing receptors. CCR8+CD4+ cells express CCR7 and CD62L and are present in spleen and lymph nodes of mice. Approximately 25% of CCR8+CD4 T cells express CD25high while 20% of CCR8+CD4+ express the T regulatory cell transcription factor FOXP3 accounting for 60% of all FOXP3-expressing CD4+ T cells. In conclusion, CCR8 marks a diverse subset of CD4 memory T cells enriched for T regulatory and Th2 cells which have the potential for recruitment into sites of allergic inflammation where they could participate in the induction and regulation of the allergic response.

Interindividual variation in human T regulatory cells

“…In this regard, it is interesting to note that there is more interindividual variability in FOXP3 protein than in FOXP3 mRNA and only a minor relationship between the two, suggesting translational or posttranslational control. Some of these potential modulators of FOXP3 include genes such as CCR8 or CD101, which do not belong to the Treg signature but have been previously tied to Foxp3 expression and/or Treg potency (51,52), and several genes involved with lipid uptake and metabolism (LDLR, TRIB1), possibly reflecting a role in cellular lipids in controlling FOXP3, or genes of yet unrecognized relevance that may warrant further exploration (CD93, MGAT4A). Interestingly, CCR8 or CD101 seem to correlate with FOXP3 protein but not mRNA, possibly suggesting that they are involved with FOXP3 posttranslational regulation.…”

IgG4-related sclerosing cholangitis: all we need to know

“…These two molecules are probably important because 50 % of Th2 lymphocytes and 60 % of FOXP3? Tregs express CCR8 [117]. CCL1 is expressed in the ductal and glandular epithelia in ISC.…”

Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

“…IRF4-deficient Tregs fail to regulate CCR8, an important chemokine receptor involved in effector T cell and Treg migration towards the lungs and skin during a Th2 response [7,30]. It is therefore possible that IRF4 in Tregs acts in a similar manner to Bcl6 and T-bet, by transiently modifying Treg migration in response to microenvironmental signals.…”