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Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis.

ABSTRACT: The signaling pathways utilized by naïve and experienced effector CD4 T cells during activation and proliferation were evaluated. While inhibition of either mTOR or MAPK alone was able to inhibit naïve T cell proliferation, both mTOR and MAPK (ERK) pathway inhibition was required to efficiently block experienced, effector CD4 T cell proliferation. This was demonstrated both in vitro, and in vivo by treating mice with collagen-induced arthritis using mTOR and/or ERK inhibitors. The combination of mTOR and ERK inhibition prevented or treated disease more efficiently than either agent alone. These data illustrate the different requirements of naïve and experienced effector CD4 T cells in the use of the mTOR and MAPK pathways in proliferation, and suggest that therapies targeting both the mTOR and MAPK pathways may be more effective than targeting either pathway alone in the treatment of CD4 T cell-mediated autoimmunity.

SUBMITTER: Lin JT

PROVIDER: S-EPMC3273543 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis.

Lin Jack T JT Stein Emily A EA Wong Michael T MT Kalpathy Krishna J KJ Su Leon L LL Utz Paul J PJ Robinson William H WH Fathman C Garrison CG

Clinical immunology (Orlando, Fla.) 20111001 2

The signaling pathways utilized by naïve and experienced effector CD4 T cells during activation and proliferation were evaluated. While inhibition of either mTOR or MAPK alone was able to inhibit naïve T cell proliferation, both mTOR and MAPK (ERK) pathway inhibition was required to efficiently block experienced, effector CD4 T cell proliferation. This was demonstrated both in vitro, and in vivo by treating mice with collagen-induced arthritis using mTOR and/or ERK inhibitors. The combination of ...[more]

PMID: 22075384

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Project description:Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease).

Project description:BackgroundThe genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis.ResultMonocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively.ConclusionOur data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

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Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis.

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Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis.

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