Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab

Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8+ T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8+ T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8+ T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.

Subpopulations of regulatory T-lymphocytes in the peripheral blood of patients with rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is an inflammatory rheumatic disease, associated with a dysfunction of the T cell-mediated tolerance and leading to the disability of working population. The regulatory CD4+ T cells are play important role in the regulation of autoimmunity and can suppress immune responses. With that, there is no consensus on the content of these lymphocytes and their role in the pathogenesis of RA. Objective: The aim of the study was to assess the content of peripheral blood regulatory T cells (Treg) according to the expression of membrane markers CD4, CD25, CD127 and intracellular FOXP3 marker, as well as the expression of two functional molecules (CTLA-4 and CCR4) in Treg cells of patients with RA. Methods: Peripheral blood samples of RA patients (mean age 61,1±10,5) and healthy controls (mean age 52,2±14,0) were analyzed. Cell count and the expression level of molecules were assessed by flow cytometry. Results: Peripheral blood samples of 36 RA patients and 20 healthy donors were analyzed. The number of the cells with Treg-associated phenotypes CD4+CD25hi and CD4+CD25hiCD127low/– was higher in RA patients in comparison with healthy donors. Increased levels of RA CD4+ T cells expressing FOXP3 were also observed. This may be due to increasing in the number of CD4+FOXP3+CD25- lymphocytes, whereas the content of RA CD4+FOXP3+CD25+ Treg cells was at the level of the control. The expression of the functional molecule CTLA-4 in Treg cells of patients with RA was not different from the control, while the expression level of the chemokine receptor CCR4, which provides migration of lymphocytes at sites of inflammation and barrier tissues, was significantly increased in RA patients. Conclusion: Increase in the levels of certain Treg-associated lymphocyte populations were detected in peripheral blood of RA patients. During the natural course of RA, alterations in the level of the chemokine receptor CCR4 might indicate the enhanced lymphocyte migration.

Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4

T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC–activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC–imprinted T cells protect against influenza more effectively than do gut and skin DC–imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC–activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC–activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.