Massive Thymic Deletion Results in Systemic Autoimmunity through Elimination of CD4+ CD25+ T Regulatory Cells

Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti–hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

[1]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

[2]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[3]  H. Mcdevitt,et al.  CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer , 2002, The Journal of experimental medicine.

[4]  S. Jameson,et al.  A Spontaneous CD8 T Cell-Dependent Autoimmune Disease to an Antigen Expressed Under the Human Keratin 14 Promoter1 , 2002, The Journal of Immunology.

[5]  L. Klein,et al.  Origin of regulatory T cells with known specificity for antigen , 2002, Nature Immunology.

[6]  J. Miyazaki,et al.  Generation of CD4+CD25+ Regulatory T Cells from Autoreactive T Cells Simultaneously with Their Negative Selection in the Thymus and from Nonautoreactive T Cells by Endogenous TCR Expression1 , 2002, The Journal of Immunology.

[7]  P. Allen,et al.  Dynamic visualization of a joint-specific autoimmune response through positron emission tomography , 2002, Nature Immunology.

[8]  Ralph Weissleder,et al.  Arthritis critically dependent on innate immune system players. , 2002, Immunity.

[9]  C. Janeway,et al.  Dual receptor T cells extend the immune repertoire for foreign antigens , 2002, Nature Immunology.

[10]  C. Benoist,et al.  Damage control, rather than unresponsiveness, effected by protective DX5+ T cells in autoimmune diabetes , 2001, Nature Immunology.

[11]  Paul M. Allen,et al.  Essential Role of Neutrophils in the Initiation and Progression of a Murine Model of Rheumatoid Arthritis1 , 2001, The Journal of Immunology.

[12]  Philippa Marrack,et al.  Autoimmune disease: why and where it occurs , 2001, Nature Medicine.

[13]  K. Tung,et al.  Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy1 , 2001, The Journal of Immunology.

[14]  A. Naji,et al.  Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide , 2001, Nature Immunology.

[15]  M. Jordan,et al.  Graded Deletion and Virus-Induced Activation of Autoreactive CD4+ T Cells1 , 2000, The Journal of Immunology.

[16]  Ming-Lang Zhao,et al.  Alterations in the Spinal Cord T Cell Repertoire During Relapsing Experimental Autoimmune Encephalomyelitis1 , 2000, The Journal of Immunology.

[17]  D. Fremont,et al.  Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR1 , 2000, The Journal of Immunology.

[18]  E. Unanue,et al.  Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. , 2000, Immunity.

[19]  J. Bluestone,et al.  B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. , 2000, Immunity.

[20]  Ethan M. Shevach,et al.  Suppressor Effector Function of CD4+CD25+ Immunoregulatory T Cells Is Antigen Nonspecific , 2000, The Journal of Immunology.

[21]  K. Rajewsky,et al.  From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. , 1999, Immunity.

[22]  E. Unanue,et al.  Cutting edge: negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells. , 1999, Journal of immunology.

[23]  D. Margulies,et al.  Post‐thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti‐H/K ATPase‐ reactive T cells , 1999, European journal of immunology.

[24]  J. Lafaille,et al.  Regulatory Cd4 Ϩ T Cells Expressing Endogenous T Cell Receptor Chains Protect Myelin Basic Protein–specific Transgenic Mice from Spontaneous Autoimmune Encephalomyelitis , 1998 .

[25]  P. Allen,et al.  In vivo expression of a TCR antagonist: T cells escape central tolerance but are antagonized in the periphery. , 1998, Journal of immunology.

[26]  H. von Boehmer,et al.  Allelic Inclusion of T Cell Receptor α Genes Poses an Autoimmune Hazard Due to Low-Level Expression of Autospecific Receptors , 1998 .

[27]  Kathleen M. Smith,et al.  Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. , 1997, International immunology.

[28]  D. Borchelt,et al.  Hyperaccumulation of FAD-linked presenilin 1 variants in vivo , 1997, Nature Medicine.

[29]  V. Kouskoff,et al.  Organ-Specific Disease Provoked by Systemic Autoimmunity , 1996, Cell.

[30]  B. Stockinger,et al.  Expression of a second receptor rescues self-specific T cells from thymic deletion and allows activation of autoreactive effector function. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Sakaguchi,et al.  Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation , 1996, The Journal of experimental medicine.

[32]  Y. Xia,et al.  Antigen compartmentation and T helper cell tolerance induction , 1996, The Journal of experimental medicine.

[33]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[34]  V. Kouskoff,et al.  A vector driving the expression of foreign cDNAs in the MHC class II-positive cells of transgenic mice. , 1993, Journal of immunological methods.

[35]  S. Tonegawa,et al.  Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice , 1993, Cell.

[36]  M. B. Novick,et al.  Association of a V beta 2-specific superantigen with a tumorigenic milk-borne mouse mammary tumor virus. , 1993, Journal of immunology.

[37]  H. Boehmer,et al.  Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes , 1988, Nature.

[38]  R. Good,et al.  Post-thymectomy autoimmune phenomena in mice. II. Morphologic observations. , 1969, Laboratory investigation; a journal of technical methods and pathology.

[39]  R. Good,et al.  Postthymectomy wasting associated with autoimmune phenomena. I. Antiglobulin-positive anemia in A and C57BL-6 Ks mice. , 1967 .

[40]  For April. , 1903 .