Deborah Fowell
| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Microbiology and Immunology in the Center for Vaccine Biology and Immunology |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 609
Rochester NY 14642
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| 2000 |
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| 2004 | HHMI Junior Faculty Start-up Award | Hughes | | 2000 |
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| Pew Scholars Nominee | | 2006 |
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| 2007 | Discovery Concept Fund | Johnson and Johnson | | 2007 |
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| Mary Jane Kugel Award | Juvenile Diabetes Research Foundation | | 2010 |
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| Graduate Student Society Faculty Award | | 2011 |
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| Basic Science Mentoring Award |
Regulation of Immunity at Tissue Sites of Infection and Autoimmunity
The acquisition and execution of CD4 effector function are tightly regulated and spatially compartmentalized. In the lymph node (LN), naïve CD4+ T cells acquire specialized functions by means of expression of distinct cytokines and acquire distinct homing properties. Therefore both the function and subsequent localization of effector cells appears to be pre-determined during differentiation in the LN. However, once CD4 effectors leave the lymph node their physical and functional fate is less well understood. The location and inflammatory context in which effector T cells are reactivated at the infection site are likely to determine the success of a given immune response. Our research focuses on mechanisms of immune regulation at tissue sites of inflammation.
Our studies with the protozoa Leishmania major suggest that this centrally (LN) generated effector repertoire can be further edited at the infected tissue site. Cytokine production in the inflamed tissue can be modulated at a number of levels including chemokine-driven differential recruitment of effector cells, the provision of signals for effector cell function and suppression by regulatory T cells (Tregs). The concept that tissue resident pathogens may subvert the centrally generated cytokine repertoire has important therapeutic implications. Novel therapies that focus on manipulating the local infection site to encourage appropriate recruitment or activation of effectors may be particularly beneficial.
Regulatory T cells play important immuno-modulatory roles at sites of inflammation in both infection and autoimmunity. Nonetheless, their mode of suppression remains controversial and is likely to be context dependent and modified by the inflammatory milieu. We focus on the molecular consequences of Treg encounter for the CD4+ T cells and have identified important points of control for early IL-2 production and for Th differentiation and effector function. Regulatory T cells can readily be found at sites of inflammation in infectious and autoimmune settings. It is clear that their activity also needs to be regulated in order to enable protective immunity to proceed but that these mechanisms of control may exacerbate autoimmune pathology. We are interested in the functional fate of Tregs at sites of inflammation, particularly in the context of autoimmune diabetes.
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Hyun YM, Sumagin R, Sarangi PP, Lomakina E, Overstreet MG, Baker CM, Fowell DJ, Waugh RE, Sarelius IH, Kim M. Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels. J Exp Med. 2012 Jul 2; 209(7):1349-62.
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Mock DJ, Hollenbaugh JA, Daddacha W, Overstreet MG, Lazarski CA, Fowell DJ, Kim B. Leishmania Induces Survival, Proliferation and Elevated Cellular dNTP Levels in Human Monocytes Promoting Acceleration of HIV Co-Infection. PLoS Pathog. 2012 Apr; 8(4):e1002635.
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Huang YH, Sojka DK, Fowell DJ. Cutting Edge: Regulatory T Cells Selectively Attenuate, Not Terminate, T Cell Signaling by Disrupting NF-?B Nuclear Accumulation in CD4 T Cells. J Immunol. 2012 Feb 1; 188(3):947-51.
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Sojka DK, Fowell DJ. Regulatory T cells inhibit acute IFN-? synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10. Proc Natl Acad Sci U S A. 2011 Nov 8; 108(45):18336-41.
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Singleton KL, Gosh M, Dandekar RD, Au-Yeung BB, Ksionda O, Tybulewicz VL, Altman A, Fowell DJ, Wülfing C. Itk controls the spatiotemporal organization of T cell activation. Sci Signal. 2011 Oct 4; 4(193):ra66.
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Hughson A, Bromberg I, Johnson B, Quataert S, Jospe N, Fowell DJ. Uncoupling of proliferation and cytokines from suppression within the CD4+CD25+Foxp3+ T-cell compartment in the 1st year of human type 1 diabetes. Diabetes. 2011 Aug; 60(8):2125-33.
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Sahu N, Morales JL, Fowell D, August A. Modeling susceptibility versus resistance in allergic airway disease reveals regulation by Tec kinase Itk. PLoS One. 2010; 5(6):e11348.
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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.
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Sojka DK, Hughson A, Fowell DJ. CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation. Eur J Immunol. 2009 Jun; 39(6):1544-51.
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Fowell DJ. Signals for the execution of Th2 effector function. Cytokine. 2009 Apr; 46(1):1-6.
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Sojka DK, Lazarski CA, Huang YH, Bromberg I, Hughson A, Fowell DJ. Regulation of immunity at tissue sites of inflammation. Immunol Res. 2009; 45(2-3):239-50.
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Lazarski CA, Hughson A, Sojka DK, Fowell DJ. Regulating Treg cells at sites of inflammation. Immunity. 2008 Oct 17; 29(4):511; author reply 512.
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Sojka DK, Huang YH, Fowell DJ. Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology. 2008 May; 124(1):13-22.
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Katzman SD, Fowell DJ. Pathogen-imposed skewing of mouse chemokine and cytokine expression at the infected tissue site. J Clin Invest. 2008 Feb; 118(2):801-11.
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Zhao X, Zheng B, Huang Y, Yang D, Katzman S, Chang C, Fowell D, Zeng WP. Interaction between GATA-3 and the transcriptional coregulator Pias1 is important for the regulation of Th2 immune responses. J Immunol. 2007 Dec 15; 179(12):8297-304.
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Au-Yeung BB, Fowell DJ. A key role for Itk in both IFN gamma and IL-4 production by NKT cells. J Immunol. 2007 Jul 1; 179(1):111-9.
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Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol. 2006 Nov 15; 177(10):6780-6.
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Sukiennicki TL, Fowell DJ. Distinct molecular program imposed on CD4+ T cell targets by CD4+CD25+ regulatory T cells. J Immunol. 2006 Nov 15; 177(10):6952-61.
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Au-Yeung BB, Katzman SD, Fowell DJ. Cutting edge: Itk-dependent signals required for CD4+ T cells to exert, but not gain, Th2 effector function. J Immunol. 2006 Apr 1; 176(7):3895-9.
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Sojka DK, Hughson A, Sukiennicki TL, Fowell DJ. Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity. J Immunol. 2005 Dec 1; 175(11):7274-80.
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Morales-Tirado V, Johannson S, Hanson E, Howell A, Zhang J, Siminovitch KA, Fowell DJ. Cutting edge: selective requirement for the Wiskott-Aldrich syndrome protein in cytokine, but not chemokine, secretion by CD4+ T cells. J Immunol. 2004 Jul 15; 173(2):726-30.
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Gurunathan S, Stobie L, Prussin C, Sacks DL, Glaichenhaus N, Iwasaki A, Fowell DJ, Locksley RM, Chang JT, Wu CY, Seder RA. Requirements for the maintenance of Th1 immunity in vivo following DNA vaccination: a potential immunoregulatory role for CD8+ T cells. J Immunol. 2000 Jul 15; 165(2):915-24.
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Pippig SD, Peña-Rossi C, Long J, Godfrey WR, Fowell DJ, Reiner SL, Birkeland ML, Locksley RM, Barclay AN, Killeen N. Robust B cell immunity but impaired T cell proliferation in the absence of CD134 (OX40). J Immunol. 1999 Dec 15; 163(12):6520-9.
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Heath VL, Hutchings P, Fowell DJ, Cooke A, Mason DW. Peptides derived from murine insulin are diabetogenic in both rats and mice, but the disease-inducing epitopes are different: evidence against a common environmental cross-reactivity in the pathogenicity of type 1 diabetes. Diabetes. 1999 Nov; 48(11):2157-65.
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Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, Locksley RM. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity. 1999 Oct; 11(4):399-409.
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Fowell DJ, Locksley RM. Leishmania major infection of inbred mice: unmasking genetic determinants of infectious diseases. Bioessays. 1999 Jun; 21(6):510-8.
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Pingel S, Launois P, Fowell DJ, Turck CW, Southwood S, Sette A, Glaichenhaus N, Louis JA, Locksley RM. Altered ligands reveal limited plasticity in the T cell response to a pathogenic epitope. J Exp Med. 1999 Apr 5; 189(7):1111-20.
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Locksley RM, Pingel S, Lacy D, Wakil AE, Bix M, Fowell DJ. Susceptibility to infectious diseases: Leishmania as a paradigm. J Infect Dis. 1999 Mar; 179 Suppl 2:S305-8.
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Wakil AE, Wang ZE, Ryan JC, Fowell DJ, Locksley RM. Interferon gamma derived from CD4(+) T cells is sufficient to mediate T helper cell type 1 development. J Exp Med. 1998 Nov 2; 188(9):1651-6.
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Fowell DJ, Bix M, Shinkai K, Lacy D, Locksley RM. Disease susceptibility and development of the cytokine repertoire in the murine Leishmania major model. Eur Cytokine Netw. 1998 Sep; 9(3 Suppl):102-6.
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Reiner SL, Fowell DJ, Moskowitz NH, Swier K, Brown DR, Brown CR, Turck CW, Scott PA, Killeen N, Locksley RM. Control of Leishmania major by a monoclonal alpha beta T cell repertoire. J Immunol. 1998 Jan 15; 160(2):884-9.
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Locksley RM, Fowell DJ, Shinkai K, Wakil AE, Lacy D, Bix M. Development of CD4+ effector T cells and susceptibility to infectious diseases. Adv Exp Med Biol. 1998; 452:45-52.
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Hagenbaugh A, Sharma S, Dubinett SM, Wei SH, Aranda R, Cheroutre H, Fowell DJ, Binder S, Tsao B, Locksley RM, Moore KW, Kronenberg M. Altered immune responses in interleukin 10 transgenic mice. J Exp Med. 1997 Jun 16; 185(12):2101-10.
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Fowell DJ, Magram J, Turck CW, Killeen N, Locksley RM. Impaired Th2 subset development in the absence of CD4. Immunity. 1997 May; 6(5):559-69.
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Saoudi A, Seddon B, Fowell D, Mason D. The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into prediabetic recipients. J Exp Med. 1996 Dec 1; 184(6):2393-8.
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Brown DR, Fowell DJ, Corry DB, Wynn TA, Moskowitz NH, Cheever AW, Locksley RM, Reiner SL. Beta 2-microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses. J Exp Med. 1996 Oct 1; 184(4):1295-304.
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Ramírez F, Fowell DJ, Puklavec M, Simmonds S, Mason D. Glucocorticoids promote a TH2 cytokine response by CD4+ T cells in vitro. J Immunol. 1996 Apr 1; 156(7):2406-12.
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Heath VL, Saoudi A, Seddon BP, Moore NC, Fowell DJ, Mason DW. The role of the thymus in the control of autoimmunity. J Autoimmun. 1996 Apr; 9(2):241-6.
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Saoudi A, Seddon B, Heath V, Fowell D, Mason D. The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol Rev. 1996 Feb; 149:195-216.
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Fowell DJ, Wakil AE, Locksley RM. Interleukin-12 in murine leishmaniasis--match, flame or fuel? Res Immunol. 1995 Sep-Oct; 146(7-8):566-75.
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Fowell D, Powrie F, Saoudi A, Seddon B, Heath V, Mason D. The role of subsets of CD4+ T cells in autoimmunity. Ciba Found Symp. 1995; 195:173-82; discussion 182-8.
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Locksley RM, Wakil AE, Corry DB, Pingel S, Bix M, Fowell DJ. The development of effector T cell subsets in murine Leishmania major infection. Ciba Found Symp. 1995; 195:110-7; discussion 117-22.
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Cyster JG, Fowell D, Barclay AN. Antigenic determinants encoded by alternatively spliced exons of CD45 are determined by the polypeptide but influenced by glycosylation. Int Immunol. 1994 Dec; 6(12):1875-81.
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Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med. 1993 Mar 1; 177(3):627-36.
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Mason D, Fowell D. T-cell subsets in autoimmunity. Curr Opin Immunol. 1992 Dec; 4(6):728-32.
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Fowell D, McKnight AJ, Powrie F, Dyke R, Mason D. Subsets of CD4+ T cells and their roles in the induction and prevention of autoimmunity. Immunol Rev. 1991 Oct; 123:37-64.
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Powrie F, Fowell D, McKnight AJ, Mason D. Lineage relationships and functions of CD4+ T-cell subsets in the rat. Res Immunol. 1991 Jan; 142(1):54-8.
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