Joseph Craft, M.D.

Professor of Medicine, Chief of Rheumatology
Professor of Immunobiology and Director of Investigative Medicine
Rheumatology

Research Activities

We seek to define the mechanisms of loss of self-tolerance and activation of autoreactive T cells in systemic autoimmune diseases and their capacity to propagate and to regulate autoreactive B cell help for pathogenic autoantibody production. In ongoing and published studies, we have demonstrated that T cells from mice with systemic autoimmune syndromes, such as lupus, are hyper-responsive to activation through their antigen receptors, compared to T cells from non-autoimmune animals, with this difference apparently an intrinsic (genetic) one.

In more recent work, we have identified novel, and separable, CD4+ T cell subsets that promote autoantibody help and peripheral inflammation in autoimmunity. The former cells are characterized by unique surface markers and cytokine production, including IL-21, and localize in secondary lymphoid tissues in the germinal center and extrafollicular foci, sites of B cell maturation and chronic antibody production in autoimmunity and chronic inflammation. Ongoing analysis of this population includes identification of their unique co-stimulatory requirements, as well as production of gene-modified reporter mice to allow studies of trafficking and in situ communication. The latter CD4+ inflammatory cells are marked by unique chemokine receptor expression, cytokine production, and peripheral trafficking, including to sites of organ injury in systemic autoimmunity. Ongoing studies are targeted towards identification of the developmental pathway of this inflammatory subset, dissection of their potential to produce inflammation in autoimmune and inflammatory contexts, and characterization of the intrinsic and extrinsic factors that promote their development versus those cells that selectively provide ongoing B cell help.

Selected Publications

• Vratsanos G, Jung S, Park Y-M, Craft J. CD4+ T cells from lupus-prone mice are hyper-responsive to TCR engagement: A model to explain spontaneous T cell activation in lupus. J Exp Med 193:329-337, 2001.
• Shlomchik M, Craft J, Mamula M. From T to B and back again: Positive feedback in systemic autoimmune disease. Nature Rev Immunol 1:147-153, 2001.
• Yin Z, Chen C-H, Szabo S, Glimcher LH, Ray A, Craft J. T-bet dominance over GATA-3 leads to default production of IFN-gamma in gamma delta T cells. J Immunol 168:1566-1571, 2002.
• Yin Z, Bahtiyar G, Zhang N, Liu L, Zhu P, Robert M, McNiff J, Madaio MP, Craft J. IL-10 is a regulatory cytokine in murine lupus J Immunol 169:2148-2155, 2002.
• Bouzahzah F, Jung S, Craft J. CD4+ T cells from lupus-prone mice avoid antigen specific tolerance induction in vivo. J Immunol 170:741-748, 2003.
• Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, Craft J, Yin Z. gamma delta T cells provide an early source of IFN-gamma in tumor immunity. J Exp Med 198:433-442, 2003.
• Wang T, Scully E, Yin Z, Kim J-H, Wang S, Yan J, Mamula M, Anderson J, Craft J, Fikrig E. IFN-gamma producing gamma delta T cells help control murine West Nile virus infection. J Immunol 171:2524-2533, 2003.
• Ramsburg E, Tigelaar R, Craft J, Hayday A. Age-dependent requirement for gamma delta T cells in the primary but not secondary protective immune response against an intestinal parasite. J Exp Med 198:1403-1414, 2003.
• Kang I, Quan T, Nolasco H, Park S-H, Hong M S, Crouch J, Pamer EG, Howe JG, Craft J. Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J Immunol 172:1287-1294, 2004.
• Kong PL, Morel L, Croker B, Craft J. The centromeric region of chromosome 7 from MRL mice (Lmb3) is an epistatic modifier of Fas for autoimmune disease expression. J Immunol 172:2785-2794, 2004.
• Kang I, Hong M-S, Nolasco H, Park S-H Dan J, Craft J. Age-associated change in the homeostasis of memory CD4+ T cells impairs long-term CD4+ T cell responses to influenza vaccine. J Immunol 172:7399-7407, 2004.
• Choi JY, Craft J. Activation of naïve CD4+ T cells in vivo by a self-peptide mimic: Mechanism of tolerance maintenance and preservation of immunity. J Immunol 173: 673-681, 2004.
• Zielinski C, Jacob S, Bouzahzah F, Ehrlich B, Craft, J. Naive CD4+ T cells from lupus-prone MRL mice display TCR-mediated hyper-proliferation due to intrinsic threshold defects in activation. J Immunol 174:5100-9, 2005.
• Wang T, Gao Y, Scully E, Davis CT, Anderson JF, Barrett A, Ledizet M, Koski R, Yin Z, Craft J, Fikrig E. gamma delta T cells facilitate adaptive immunity against West Nile virus infection. J Immunol 177:1825-1832, 2006.
• Choi J, Gao W, Odegard J, Shiah HS, Kashgarian M, McNiff J, Baker D, Cheng Y, Craft J. A novel Tylophorine analog that inhibits NF-kappaB abrogates skin disease in lupus-prone MRL-Faslpr mice. Arth Rheum 54:3277–3283, 2006.
• Chen L, Kim ST, He W, Tao J, Gao Y, Chi H, Intlekofer AM, Harvey B, Reiner SL, Yin Z, Flavell R, Craft J. Both epigenetic and transcriptional programs lead to default IFN-gamma production by gamma delta T cells. J Immunol 178:2730-2736, 2007.

Assistant Administrator
Anne Kellett	(203) 785-7063
Lab Manager
Ping Zhu	(203) 785-7657
Graduate Students
Sairy Hernandez	(203) 737-4240
Heba Nowyhed	(203) 737-4240
Postdoctoral Associates/Fellows
Leah Diplacido, Ph.D.	(203) 737-4240
Xuemei Dong, Ph.D.	(203) 737-4240
Sang Taek Kim, M.D.	(203) 737-4240
Begoña Lainez, Ph.D.	(203) 737-4240
Amanda Poholek, Ph.D.	(203) 737-4240
Jason Weinstein, Ph.D.	(203) 737-4240
Associate Research Scientists
Jin-Young Choi, Ph.D.	(203) 737-4240
Jian Tao, Ph.D.	(203) 737-4240

Contact

Campus Address
300 Cedar Street
TAC S-541D

Mailing Address
Yale University School of Medicine
P.O. Box 208031
New Haven, CT 06520-8031

E-mail
joseph.craft@yale.edu

Office Phone
(203) 785-7063

Fax
(203) 785-5415