Research

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Lymphocyte Cell Biology Section

John O'Shea, M.D.
Section Chief, Lymphocyte Cell Biology Section
Molecular Immunology and Inflammation Branch (MIIB)
Phone: (301) 496-6026
Fax: (301) 402-0012
E-mail: osheajo@mail.nih.gov

Research Overview

The Lymphocyte Cell Biology Section (LCBS) studies the molecular basis by which cytokines, the extracellular messengers of the immune system, regulate the development and function of lymphocytes and other immune cells. By studying how engagement of cytokine receptors transduces signals, which in turn regulate transcription factors and epigenetic events to modulate gene expression, we hope to more deeply understand how T cells participate in host defense and contribute to the pathogenesis of immune-mediated diseases. These insights are used to facilitate the development of new therapeutic targets.

Multiple Pathways CD4+ T Cell differentiation. Figure showing extensive communication between innate and adaptive arms of the immune system.

Host defense against pathogenic micro-organisms requires extensive communication between innate and adaptive arms of the immune system. Signals from innate immune cells, induced by pathogens and inflammatory stimuli, drive naive CD4+ T cells to differentiate into one of several effector fates including T helper 1 (Th1), Th2, and Th17 cells (see Pathway Figure). The products of differentiated T cells subsequently orchestrate immune responses to effectively eliminate pathogens. Other stimuli cause CD4+ T cells to become regulatory T (Treg) cells, which dampen immune responses. These effector and regulatory CD4+ T cell lineages protect the body from infection when appropriately activated but can also contribute to the pathogenesis of autoimmune diseases.

We now know that the cytokines produced by innate immune cells are critical for the development and polarization of CD4 subsets. Cytokine receptors associate with a class of protein tyrosine kinases termed Janus kinases or Jaks. The Lymphocyte Cell Biology Section cloned human Jak3, a kinase predominantly expressed in immune and hematopoietic cells, and demonstrated that Jak3 associates with the common γ chain (γc). This is shared cytokine receptor is used by interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21 and mutations of JAK3 were shown to underlie autosomal recessive severe combined immunodeficiency. Patients suspected of having Jak3 mutations or other problems may be seen at the NIH Clinical Center under Protocol 99 AR0004. Because Jak3's critical function in immune cells, compound Jak3 inhibitors have been developed as a new class of immunosuppressive drugs. The NIH holds a patent related to antagonizing Jaks (United States Patent 7,070,972 Janus family kinases and identification of immune modulators -- NIAMS also has an ongoing Cooperative Research And Development Agreement (CRADA) with Pfizer, which is part of the ongoing work dedicated to understanding the actions of a Jak3 inhibitor in vivo.

Upon activation, Jaks phosphorylate receptor subunits, thereby providing docking sites for downstream signaling molecules, such as the signal transducers and activators of transcription (STATs). STATs bind to the phosphorylated receptors and become phosphorylated, allowing them to dimerize, translocate to the nucleus, and regulate gene expression. The LCBS demonstrated that IL-12 activates STAT4, a key factor that initiates the development of Th1 cells that produce the signature cytokine interferon-γ (IFN-γ). A relatively new effector CD4+ T cell lineage that selectively produces IL-17 has recently been recognized. Cytokines that promote Th17 cell differentiation signal through STAT3 and the LCBS showed that Th17 cell differentiation is dependent upon this transcription factor. Importantly, the disorder Job's or HyperIgE syndrome is due to mutations of Stat3. LCBS in collaboration with other NIH scientists showed that a major defect in this disorder is impairment of Th17 cell generation.

In addition to Th cells, regulatory T (Treg) cells represent another important immunoregulatory subset of CD4+ T cells. LCBS showed that Stat5 is critical for Treg cell differentiation, and binds to the gene encoding the transcription factor Foxp3. Ongoing work in the lab is devoted to further investigating the role of STAT3, STAT4 and STAT5 in Th cell differentiation, host defense and autoimmunity. The LCBS has used microarray technology to define the STAT target genes induced by cytokines, such as Map3k8 and Furin. Most recently, LCBS has used chromatin immunoprecipitation and massive parallel sequencing to map epigenetic modifications in CD4+ T cells. We are intensively studying the interplay between STAT family transcription factors and epigenetic events, as they relate to gene expression in developing helper T cells.

Selected Publications

Ghoreschi K, Laurence A, O'Shea JJ. Selectivity and therapeutic inhibition of kinases: to be or not to be?. Nat Immunol. 2009 Apr;10(4):356-60. Epub 2009 Mar 19. Review.

McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O'Shea JJ, Cua DJ. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing e ffector T helper cells in vivo. Nat Immunol. 2009 Mar;10(3):314-24. Epub 2009 Feb 1.

Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009 Mar;228(1):273-87.

Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov II, Littman DR, O'Shea JJ. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med. 2009 Jan 16;206(1):35-41.

Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT, Schones DE, Peng W, Sun HW, Paul WE, O'Shea JJ, Zhao K. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009 Jan;30(1):155-67.

Watford WT, Hissong BD, Durant LR, Yamane H, Muul LM, Kanno Y, Tato CM, Ramos HL, Berger AE, Mielke L, Pesu M, Solomon B, Frucht DM, Paul WE, Sher A, Jankovic D, Tsichlis PN, O'Shea JJ. Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med. 2008 Nov 24;205(12):2803-12.

Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, Andersson J, Shevach EM, Quezado M, Bouladoux N, Roebroek A, Belkaid Y, Creemers J, O'Shea JJ. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature. 2008 Aug 13.

Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O'Shea JJ, Shevach EM. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 2008 Sep 1;205(9):1975-81. Epub 2008 Aug 18.

Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008 Apr 10;452(7188):773-6. Epub 2008 Mar 12.

Wei L, Laurence A, Elias KM, O'Shea JJ. IL-21 is produced by TH17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem. 2007 Nov 30;282(48):34605-10. Epub 2007 Sep 20.

Chen Z, Tato CM, Muul L, Laurence A, O'Shea JJ. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 2007 Sep;56(9):2936-46.

Laurence A*, Tato CM*, Davidson TS*, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O'Shea JJ. *Joint first authorship Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation. Immunity. 2007 Mar;26(3):371-81.

Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O'Shea JJ. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev. 2005; 203:127-42.

O'Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov. 2004; 3(7):555-64.

See complete list of publications

Updated February 4, 2009