Upon antigen challenge, CD4+ (helper) T cells develop from uncommitted precursors into terminally differentiated effector T cells characterized by discrete cytokine gene expression patterns. Th1 effectors (via interferon-gamma and lymphotoxin production) efficiently confront intracellular pathogens through activation of phagocytes and cytotoxic lymphocytes. Conversely, Th2 effectors (via interleukin-4 (IL-4) IL-5 and IL-13 secretion) mediate mucosal immunity and the expulsion of intestinal helminths. Importantly, Th1 and Th2 cells antagonize the growth and biological effects of one another leading to highly polarized populations on immune challenge. Many disease states, both autoimmune and infectious, result from the development of a robust immune response that has been inappropriately polarized. We are interested in how these effector populations are established. Our data suggests multiple check points in effector differentiation, at least one at the level of T cell signaling on initial activation and one at the population level for expansion and survival of effectors.

A critical component of the immune system is tight regulation; ensuring appropriate termination of immune responses following pathogen clearance and avoiding the inappropriate activation of immune responses to self tissues resulting in autoimmunity. Regulation is in part mediated by a distinct CD4+ T lineage called regulatory T cells (T regs). Removal of T regs from the immune system renders rodents susceptible to multiple autoimmune diseases. We are interested in the signals that drive differentiation of T regs and the mechanisms of their regulatory activity.

We exploit the genetics of susceptibility to disease in inbred mouse strains to uncover important cellular and molecular components of effector T cell development. Our current studies focus on the basic mechanisms that regulate effector T cell differentiation, including:

• Lymphocyte signaling for effector lineage commitment (Immunity 11:399, Immunity 6:559)
  
  
• Development of immune responses in vivo following parasite infection (Bioessays 21:510)
  
  
• Development and activity of regulatory T cells in prevention of autoimmune disease.

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. 173:726-30, 2004.

Mosmann T, Fowell DJ. The Th1/Th2 paradigm in infections. Editors: Kaufmann SHE, Sher A, Ahmed R: Immunology of Infectious Diseases. ASM Press, 2001.

Gurunathan S, Stobie L, Prussin C, Sacks DL, Glaichenhaus N, 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. 165:915-24, 2000.

Pippig SD, Pena-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. 163:6520-9, 1999.

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. 48:2157-65, 1999.

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 11:399-409, 1999.

Fowell DJ, Locksley RM. Leishmania major infection of inbred mice: unmasking genetic determinants of infectious diseases. BioEssays 21:510-8, 1999.

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 189:1111-20, 1999.

Locksley RM, Pingel S, Lacy D, Wakil AE, Bix M, Fowell DJ. Susceptibility to infectious disease: Leishmania as a paradigm. J Infect Dis 179 Suppl 2:S305-8, 1999.

Fowell DJ, Magram J, Turck CW, Killeen N, Locksley RM. Impaired Th2 development in the absence of CD4. Immunity 6:559-69, 1997.