Th Cell Differentiation

Project Description

T helper cell activation and differentiation to functionally distinct subsets

Selective activation of T helper (Th) cell subsets plays an important role in the pathogenesis of human allergy and inflammatory diseases. Dissecting pathways and regulatory networks leading to the development of Th1 or Th2 cells will be crucial to understand the pathogenesis of allergy and inflammatory diseases. Improved understanding may lead to better strategies for developing diagnostics and effective therapies for these diseases.

Cytokines IL-12 and IL-4 selectively regulate the development and differentiation of CD4+ T cell subsets to IFN-? and IL-2 producing Th1 cells or IL-4 and IL-5 secreting Th2 cells, respectively. Th2 cytokines lead to a series of inflammatory processes characteristic for asthma and other atopic diseases (e.g. production of IgE, mast cell and eosinophil activation). Th1 cells, on the other hand, play a role in the pathogenesis of autoimmune diseases (e.g. type I diabetes). IL4R activation leads to activation of Signal Transducer and Activator of Transcription (STAT) protein 6. STAT6-/- mice are unable to mount a Th2 or an IgE response and are resistant to antigen induced airway inflammation and airway hyperresponsiveness, emphasizing the key role IL4R/STAT6 signalling in asthma.

We were among the first to report functionally distinct Th1 and Th2 subsets in human. During the past few years our studies have focused on signaling and transcriptional regulation of lymphocyte activation and differentiation.

Applying a holistic approach to identify genes involved in the process we have profiled gene expression during Th cell activation and differentiation both in human and in mouse. Importantly, our recent data indicate substantial differences in the regulation of gene expression during human Th cell differentiation when compared to that in mouse Th cells.

Our recent results have led to novel hypotheses on the key factors involved in human Th cell differentiation. We are currently focusing at elucidating the function of the novel genes and pathways identified in our studies with primary human CD4+ T cells. Detailed analysis of upstream T cell Receptor (TCR)/key cytokine receptor induced signaling pathways and regulatory circuits includes repeated rounds of mathematical modelling and experimental verification. In parallel, the signalling and transcriptional protein complexes are analysed with state-of-the-art proteomics, mass spectrometry and cell imaging techniques to build a model of T cell activation and differentiation.

Integrating quantitative data on T cell activation and differentiation will increase our understanding of these processes central for human health and disease and provide novel insights into new therapeutic interventions.

Team Members

Group Leader

Riitta Lahesmaa, M.D., Ph.D., Professor

Visiting Professors/Scientists

Anjana Rao, Ph.D., La Jolla Institute for Allergy & Immunology
Kanury Rao, Ph.D., International Centre for Genetic Engineering and Biotechnology, New Delhi
Cisca Wijmenga, University of Groningen

Senior Scientists/Postdoctoral Fellows

Tanja Buchacher, Ph.D.
Henna Kallionpää, Ph.D.
Lingjia Kong, Ph.D.
Niina Lietzen, Ph.D.
Robert Moulder, Ph.D.
Senthil Palani, Ph.D.
Omid Rasool, Ph.D., Adjunct Professor
Subhash Tripathi, Ph.D.
Ubaid Ullah, Ph.D.

Ph.D. Students

Bilal Andrabi, M.Sc.
Santosh Bhosale, M.Sc.
Karoliina Hirvonen, M.Sc.
Kartiek Kanduri, M.Sc.
Mohd Moin Khan, M.Sc.
Essi Laajala, M.Sc. (tech)
Verna Salo, M.Sc.

Undergraduate Students

Victoria Hinkkanen
Elina Komsi

Technicians

Marjo Hakkarainen
Sarita Heinonen
Päivi Junni

Collaborators

Aebersol Ruedi, ETHZ, Zürich, Switzerland
Burge Christopher, MIT, Cambridge, USA
Gstaiger Matthias, ETHZ, Zürich, Switzerland
Lähdesmäki Harri, Tampere University of Technology and Aalto University
Rao Anjana, Immune Disease Institute, Harvard Medical School, Boston, USA
Rao Kanury, ICGEB, Delhi, India
Ren Bing, Ludwig Institute for Cancer Research, University of California, San Diego, USA

Publications

O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4(+) T helper cell differentiation. (2011) Nature Reviews Immunology, 11:239-250

Elo LL, Järvenpää H, Tuomela S, Raghav S, Ahlfors H, Laurila K, Gupta B, Lund RJ, Tahvanainen J, Hawkins RD, Oresic M, Lähdesmäki H, Rasool O, Rao KV, Aittokallio T, Lahesmaa R. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity. 2010 32:852-62

Ahlfors H, Limaye A, Elo-Uhlgrén L, Notani D, Gottimukkala K, Burute M, Tuomela S, Rasool O, Galande S* & Lahesmaa R*.  SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation. Submitted. *Equal contribution. Blood. 2010 116:1443-53.

Moulder R*, Lönnberg T*, Filén J-J, Elo L, Rainio E, Corthals G, Oresic M, Nyman TA, Aittokallio T, Lahesmaa R (*equal contribution). Quantitative Proteomics Analysis of the Nuclear Fraction of Human CD4+ Cells in the Early Phases of IL-4 Induced Th2 Differentiation. Molecular Cellular Proteomics. 2010 9:1937-53.

Filén S, Ylikoski E, Tripathi S, West A, Björkman M, Nyström J, Ahlfors H, Coffey E, Rao KV, Rasool O, Lahesmaa R. Activating transcription factor 3 is a positive regulator of human IFNG gene expression. J Immunol. 2010 May 1;184(9):4990-9.

Cho SH, Goenka S, Henttinen T, Gudapati P, Reinikainen A, Lahesmaa R, Boothby M.PARP-14, a member of the B aggressive lymphoma (BAL) family, transduces survival signals in primary B cells. Blood. 2009 Mar 12;113(11):2416-25.

Oresic M, Simell S, Sysi-Aho M, Näntö-Salonen K, Seppänen-Laakso T, Parikka V, Katajamaa M, Hekkala A, Mattila I, Keskinen P, Yetukuri L, Reinikainen A, Lähde J, Suortti T, Hakalax J, Simell T, Hyöty H, Veijola R, Ilonen J, Lahesmaa R, Knip M, Simell O. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med. 2008 Dec 22;205(13):2975-84.

Rautajoki K, Tuomela S, Moulder R, Nyman T, Lahesmaa R. Identification of novel Stat6 regulated proteins in IL-4 treated mouse lymphocytes. Proteomics. 2009 Feb;9(4):1087-98.

Tahvanainen J, Kallonen T, Lähteenmäki H, Heiskanen K, Westermarck J, Rao KV and Lahesmaa R. PRELI is a mitochondrial regulator of human primary T helper cell apoptosis, STAT6 and Th2 cell differentiation. Blood. 2009 Feb 5;113(6):1268-77.

Filén JJ, Filén S, Moulder R, Tuomela S, Ahlfors H, West A, Kouvonen P, Kantola S, Björkman M, Katajamaa M, Rasool O, Nyman TA, Lahesmaa R. Quantitative proteomics reveals GIMAP family proteins 1 and 4 to be differentially regulated during human T helper cell differentiation. Mol Cell Proteomics. 2009 Jan; 8(1): 32–44.

Kumar D, Srikanth R, Ahlfors H, Lahesmaa R, Rao KV. Capturing cell-fate decisions from the molecular signatures of a receptor-dependent signaling response. Molecular Systems Biology, 2007:3:150. 

Lund RJ*, Loytomaki M*, Naumanen T, Dixon C, Chen Z, Ahlfors H, Tuomela S, Tahvanainen J, Scheinin J, Henttinen T, Rasool O, Lahesmaa R. Genome Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation. J Immunol. 2007Mar 15;178(6):3648-60. *Equal contribution

Rautajoki KJ, Marttila EM, Nyman TA, Lahesmaa R.  IL-4 inhibits caspase-3 by regulating several proteins in the Fas pathway during initial stages of human Th2 cell differentiation. Mol Cell Proteomics. 2007 Feb;6(2):238-251.

Hahtola S, Tuomela S, Elo L, Hakkinen T, Karenko L, Nedoszytko B, Heikkila H, Saarialho-Kere U, Roszkiewicz J, Aittokallio T, Lahesmaa R, Ranki A. Th1 response and cytotoxicity genes are down-regulated in cutaneous T-cell lymphoma. Clin Cancer Res. 2006, 12(16):4812-21.

Tahvanainen J, Pykalainen M, Kallonen T, Lahteenmaki H, Rasool O, Lahesmaa R. Enrichment of nucleofected primary human CD4+ T cells: a novel and efficient method for studying gene function and role in human primary T helper cell differentiation. J Immunol Meth 2006, 310(1-2):30-9.

Pykäläinen M, Kinos R, Valkonen S, Rydman P, Kilpeläinen M,  Laitinen LA, Karjalainen J, Nieminen M, Hurme M, Kere J, Laitinen T, Lahesmaa R. Association analysis of common variants of STAT6, GATA3, and STAT4 to asthma and high serum IgE phenotypes. J Allergy Clin Immunol. 2005 115:80-7.

Lund R, Chen Z, Scheinin J, Lahesmaa, R. Early target genes of IL-12/STAT4 signaling in T helper cells. J. Immunol., 2004;  172:6775-82.

Lund, R, Aittokallio, T, Nevalainen, O and Lahesmaa, R. Identification of novel genes regulated by IL-12, IL-4 and TGFb during the early polarization of CD4+ lymphocytes. J. Immunol., 2003, 171:5328-5336.

Chen Z, Lund R, Aittokallio T, Kosonen M, Nevalainen O, Lahesmaa R. Identification of novel IL-4/Stat6-regulated genes in T lymphocytes. J Immunol., 2003, 171:3627-3635.

Hamalainen H, Zhou H, Chou W, Hashizume H, Heller R, Lahesmaa R. Distinct gene expression profiles of human type 1 and type 2 T helper cells. Genome Biol. 2001;2(7):RESEARCH0022.