Co-winner of the 2009 Melville A. Hare Research Award for the best Ph.D. thesis in Microbiology and Immunology
Dorothy Sojka graduated with a Bachelor of Science degree from the University of Illinois at Chicago. After she graduated she worked in the laboratory of Dr. Margalit Mokyr as a research assistant in the Department of Biochemistry and Molecular Biology at the University of Illinois at Chicago from 1998-2001. In 2001, as a graduate student at Georgia State University in Atlanta, GA she received a National Science Foundation fellowship and worked as a biology teacher on a BIOBUS outreach program in the Department of Biology. In 2002 she received an intramural research training award (pre-IRTA) fellowship from the National Institutes of Health and worked in the laboratory of Dr. Ronald Schwartz at the NIAID in Bethesda MD. In the fall of 2003, she attended the University of Rochester to begin graduate studies in Immunology. In 2004, she began her research on the control of CD4+ T cell function by CD4+CD25+ Regulatory T cells under the guidance of Dr. Deborah Fowell and received a PhD degree from the University of Rochester in 2009.
In the periphery thymus derived, naturally occurring CD4+CD25+Foxp3+ (Treg(s)) have the potential to suppress an extensive array of immune responses that exceed their original identification of preventing autoimmune disease. In recent years Treg mediated beneficial and harmful suppressive activities have been attributed to limiting responses to infectious agents and tumor antigens, respectively. In various immune settings Tregs have been implicated in controlling initial T cell activation, proliferation, differentiation, effector function, and migration. Although Tregs have an extensive suppressive agenda, their mechanisms of action are not well understood.
Costimulatory signals from CD28 and CTLA-4 have been identified to regulate both target T cells and Tregs and can either help the cell escape suppression or mediate the suppression. Dorothy’s work focuses on the CD4+ effector functions that are modified by Tregs in the presence of CD28 signaling as well as the role of CTLA-4 in Treg function. To get a better understanding of Treg action we first investigated the kinetics of murine Treg activity in vitro. Tregs were suppressive within a surprisingly narrow kinetic window: necessary and sufficient only in the first 6-10h of culture. Importantly, the timing of suppression was dictated by the kinetics of target T cell activation suggesting that early target T cell signals may alter susceptibility to suppression. CD28 signals enabled target T cells to resist the early Treg-induced downregulation of IL-2.
Disabling one mode of Treg suppressive activity, IL-2 secretion and proliferation, by provision of CD28 allowed us to test other arms of Treg suppressive activities. CD28 signaling abrogates Treg action through rendering the target T cell resistant to Treg suppression. We reveal that while CD28 signals do bypass the Treg blockade of IL-2 secretion and proliferation, the target cells remain susceptible to Treg suppression of IFN-γ production. The mechanism of the acute shutoff of IFN-γ production in CD4+ target cells is currently being investigated.
In a separate set of in vivo experiments we set out to test the contributions of a constitutively expressed molecule on Tregs, CTLA-4, and the role that it may play in the suppressive functions of Tregs. Although blockade of CTLA-4 interferes with Treg function, studies using CTLA-4 deficient Tregs have failed to reveal an essential requirement for CTLA-4 in Treg suppression in vivo. We demonstrate that Treg expression of CTLA-4 is essential for Treg control of lymphopenia-induced CD4+ T cell expansion. Despite IL-10 expression, CTLA-4 deficient Tregs were unable to control the expansion of CD4+ target cells in a lymphopenic environment. Moreover, unlike their WT counterparts, CTLA-4-deficient Tregs failed to inhibit cytokine production associated with homeostatic expansion and were unable to prevent colitis. Thus, while Tregs developing in the absence of CTLA-4 appear to acquire some compensatory suppressive mechanisms in vitro, we identify a non-redundant role for CTLA-4 in Treg function in vivo.
Our data reveal that Tregs have the ability to act early and suppress IL-2 secretion of CD4+ target T cells prior to the first cell division. While CD28 signals bypass the Treg blockade of IL-2 secretion and proliferation, the target T cells remain susceptible to Treg suppression of IFN-γ secretion. Therefore Tregs disable their targets through multiple mechanisms; each suppressive tool controlling a highly specific aspect of immune function.
- Morales-Tirado V, Sojka DK, Katzman SD, Lazarski CA, Finkelman FD, Urban JF, Fowell DJ. Critical requirement for the Wiskott-Aldrich syndrome protein in Th2 effector function. Blood. 2010 Apr 29;115(17):3498-507. Epub 2009 Dec 23.
- Sojka DK, Hughson A, Fowell DJ. (2009) CTLA-4 is required by CD4+CD25+ regulatory T cell to control CD4 T cell lymphopenia-induced proliferation. Eur J Immunol, Jun;39(6):1544-51
- Taylor SR, Gonzalez-Begne M, Sojka DK, Richardson JC, Sheardown SA, Harrison SM, Pusey CD, Tam FW, Elliot JI. (2009) Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses. J Leukoc Biol. Jun;85(6):978-86
- Sojka DK, Lazarski CA, Huang YH, Bromberg I, Hughson A, Fowell DJ. (2009) Regulation of immunity at tissue sites of inflammation. Immunol Res. Jan 31.
- Lazarski CA, Hughson A, Sojka DK, Fowell DJ. (2008) Regulating Treg cells at sites of inflammation. Immunity Oct;29(4):511
- Sojka DK, Huang YH, Fowell DJ. (2008) Mechanisms of regulatory T cell suppression-a diverse arsenal for a moving target. Immunology May;124(1):13-22
- Sojka DK*, Hughson A*, Sukiennicki TL, Fowell DJ. (2005) Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity. J Immunol Dec 1;175(11):7274-80
* Equal contribution