KARINE CHEMIN TEAM

T-cell immunology in rheumatic diseases: effector function and TCR diversity at the single cell level

About

Although the etiology of autoimmune diseases is unknown, a complex interplay between genetics, environment and epigenetics is proposed to be the cause of self-tolerance failure. In my team, we are interested in the function of T cells in the pathogenesis of two autoimmune diseases: rheumatoid arthritis (RA) and idiopathic inflammatory myopathies (IIM). In these two inflammatory disorders, the strongest genetic risk factor is the major histocompatibility complex (MHC) locus highlighting the importance of T cells in the pathogenesis. T cells are vital for defending the body against pathogens such as viruses and bacteria whereas, in autoimmune diseases, T cells mistakenly attack our own body. We believe that, by studying T cells at the site of inflammation, we can understand their pathogenic effector function, their antigen specificity and the mechanisms implicated in their migration and retention in the tissue. We also have a specific interest in the subset of cytotoxic CD4+ T cells sharing common effector functions with CD8+ T cells. We use single cell technologies (SmartSeq2 and 10X genomics) in association with conventional cell biology/molecular biology techniques on clinical samples to investigate the diversity of T-cell populations. Our translational research relies on strong collaborations with the Rheumatology Clinic, KI (Prof Ingrid Lundberg´s team) as well as with geneticist/bioinformatics expert (Dr. Lina Diaz-Gallo). Our ambition is to provide a better understanding of the mechanisms driving RA and IIM to improve diagnosis and clinical care.

 

Selected publications

Gerstner C, Turcinov S, Hensvold AH, Chemin K, Uchtenhagen H, Ramwadhdoebe TH, Dubnovitsky A, Kozhukh G, Rönnblom L, Kwok WW, Achour A, Catrina AI, van Baarsen LGM, Malmström V. Multi-HLA Class II Tetramer Analyses of Citrulline-Reactive T Cells and Early Treatment Response in Rheumatoid Arthritis. BMC Immunol. 2020, 18;21(1):27.

Ivanchenko LM, Aqrawi LA, Björk A, Wahren-Herlenius‎ M, and Chemin K. FOXP3+CXCR5+ CD4+ T cells frequencies are increased in peripheral blood of patients with primary Sjögren’s syndrome. Clin Exp Immunol. 2019, 195(3):305-309. 

Lloyd KA, Wigerblad G, Sahlström P, Garimella MG, Chemin K, Steen J, Titcombe PJ, Marklein B, Zhou D, Stålesen R, Ossipova E, Lundqvist C, Ekwall O, Rönnelid J, Mueller DL, Karlsson M , Skriner K, Klareskog L,Wermeling F, Malmström V, and Grönwall C. Differential ACPA binding to nuclear antigens reveals a PAD4-independent pathway and a distinct subset of autoantibodies in rheumatoid arthritis. Front Immunol. 2019, 9:3033. 

Chemin K, Ramsköld D, Diaz-Gallo L.M, Herrath J, Tandre K, Rönnblom L, Catrina A, Malmström V. EOMES-positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers. Eur J Immunol. 2018, 48(4):655-669.

Houtman M, Ekholm L, Hesselberg E, Chemin K, Malmström V, Reed A, Lundberg I, Padyukov L. (2018). T-cell transcriptomics from peripheral blood highlights differences between polymyositis and dermatomyositis patients. Arthritis Res Ther. 2018, 20(1):188.

Diaz-Gallo LM,  Ramsköld M, Shchetynsky K,  Folkersen L, Chemin K, Brynedal B, Uebe S, Okada Y,  Alfredsson L, Klareskog L, Padyukov L. Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis. Ann Rheum Dis. 2018, 77(10):1454-1462. 

Aqrawi LA, Ivanchenko M, Björk A, Ramírez Sepúlveda JI, Imgenberg-Kreuz J, Kvarnström M, Haselmayer P, Jensen JL, Nordmark G, Chemin K, Skarstein K, Wahren-Herlenius M. Diminished CXCR5 expression in peripheral blood of patients with Sjögren´s syndrome may relate to both genotype and salivary gland homing. Clin Exp Immunol. 2018, 192(3):259-270. 

Houtman M, Shchetynsky K, Chemin K, Hensvold AH, Ramsköld D, Tandre K, Eloranta ML, Rönnblom L, Uebe S, Catrina AI, Malmström V, Padyukov L. T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. J Autoimmun. 2018, 90:28-38. 

Chemin K, Pollastro S, James E, Ge C, Albrecht I, Herrath J, Gerstner C, Tandre K, Rizzi T.S, Rönnblom L, Catrina A, Holmdhal R, Klareskog L, de Vries N, Malmström V. A novel HLA-DRB110:01 restricted T cell epitope from citrullinated type II collagen relevant for Rheumatoid Arthritis. Arthritis and Rheumatology. 2016, 68(5):1124-35.

Albrecht I, Wick C, Hallgren Å, Tjärnlund A, Nagaraju K, Andrade F, Thompson K, Coley W, Phadke A, Diaz-Gallo L-M, Bottai M, Nennesmo I, Chemin K, Herrath J, Johansson K, Wikberg A, Ytterberg AJ, Zubarev RA, Danielsson O, Krystufkova O, Vencovsky J, Landegren M, Wahren-Herlenius M, Padyukov L, Kämpe O, Lundberg IE. Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies. J Clin Invest. 2015, 125(12):4612-24.

Herrath J, Chemin K, Albrecht I, Catrina AI and Malmström V. Surface expression of CD39 identifies an enriched Treg subset in the rheumatic joint, which does not suppress IL-17A secretion. Eur J Immunol. 2014, 44(10):2979-89.

Larghi P, Williamson DJ, Carpier JM, Dogniaux S, Chemin K, Bohineust A, Danglot L, Gaus K, Galli T & Hivroz C. The SNARE protein VAMP7 controls T cell activation by regulating recruitment and phosphorylation of Lat subsynaptic vesicles to the TCR actiation sites. Nature Immunology. 2013, 14(7):723-31.

Chemin K, Bohineust A, Dogniaux S, Tourret M, Guegan S, Miro F, and Hivroz, C. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J Immunol, 2012, 89(5):2159-68.

Nguyen HV, Mouly E, Chemin K, Luinaud R, Despres R, Fermand JP, Arnulf B, and Bories JC. The Ets-1 transcription factor is required for Stat1-mediated T-bet expression and IgG2a class switching in mouse B cells. Blood. 2012, 119, 4174-4181.

Husson, J., Chemin, K., Bohineust, A., Hivroz, C., and Henry, N. Force generation upon T cell receptor engagement. PLoS One 2011. 6, e19680.

Mouly E‡, Chemin K‡, Nguyen HV, Chopin M, Mesnard L, Leite-de-Moraes M, Burlen-defranoux O, Bandeira A, and Bories JC. The Ets-1 transcription factor controls the development and function of natural regulatory T cells. J Exp Med. 2010. 207(10):2113-25. 

‡ equal contribution

Tourret M., Guegan S., Chemin K., Dogniaux S., Miro F., Bohineust A., and Hivroz C. T cell polarity at the immunological synapse is required for CD154-dependent IL-12 secretion by dendritic cells. J Immunol. 2010, 185, 6809-6818. 

Picard C., Dogniaux S., Chemin K., Maciorowski Z., Lim A., Mazerolles F., Rieux-Laucat F., Stolzenberg,M.C., Debre M., Magny J.P., et al. Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity. Eur J Immunol. 2009, 39, 1966-1976. 

Nobile C., Lind M., Miro F., Chemin K., Tourret M., Occhipinti G., Dogniaux S., Amigorena, S., and Hivroz, C. Cognate CD4+ T-cell-dendritic cell interactions induce migration of immature dendritic cells through dissolution of their podosomes. Blood. 2008, 111, 3579-3590. 

Chandesris M.O., Soulier J., Labaume S., Crinquette A., Repellini L., Chemin, K., Malphettes M., Fieschi C., Asli B., Uzunhan Y., et al. Detection and follow-up of fibroblast growth factor receptor 3 expression on bone marrow and circulating plasma cells by flow cytometry in patients with t(4;14) multiple myeloma. Br J Haematol. 2007, 136, 609-614.

Eyquem S, Chemin K., Fasseu M., and Bories JC. The Ets-1 transcription factor is required for complete pre-T cell receptor function and allelic exclusion at the TCR beta locus. Proc Natl Acad Sci USA. 2004,101(44):15712-7. 

Eyquem S., Chemin K., Fasseu M., Chopin M., Sigaux F., Cumano A., Bories JC. Impaired B cell development and defective B cell receptor mediated activation in mice lacking the Ets-1 transcription factor. Eur J Immunol. 2004, 34 (11):3187-96. 

Chemin K, Gerstner C, Malmström V. Effector functions of CD4+ T cells at the site of local autoimmune inflammation - lessons from Rheumatoid Arthritis. Front Immunol Reviews. 2019, 10:353.

Chemin K, Klareskog K, Malmström V. Is RA an autoimmune disease? Current Opinion in Rheumatology. 2016, 28(2):181-8.

Hivroz C., Chemin K., Tourret M., Bohineust A. Crosstalk between T Lymphocytes and Dendritic Cells. Criticals reviews in Immunology. 2012, Vol 32, Issue 2: 139-155.

Fischer A, Picard C, Chemin K, Dogniaux S, le Deist F, Hivroz C. ZAP70: a master regulator of adaptive immunity. Semin Immunopathol. 2010, 32(2):107-16.