BADERC-Brian Wilson

Brian Wilson, MD, Ph.D.

Control of Peripheral Tolerance by CD1d-restricted T Cells

CD1d-restricted T cells (or “NKT cells”) have been reported to regulate an extremely diverse set of immunologic responses and diseases. Dysfunction of these T cells is clearly correlated with the development of autoimmunity, and in particular autoimmune diabetes. Despite the importance of CD1d-restricted T cells in this disease, how these T cells function normally and the exact nature of the disease-associated defects are unclear. While the field has focused largely on establishing functional roles for CD1d-restricted T cells in disease on a gene by gene basis, we approached this problem by using high-density oligonucleotide arrays to study CD1d-restricted clones isolated from monozygotic twin pairs discordant for type 1 diabetes. The use these of arrays was based on the hypothesis that an identification of the gene classes activated in a particular cell type would likely predict the function of that cell and potentially identify disease-related dysfunction in key regulatory circuits. When examined on the DNA microarrays, activation of CD1d-restricted T cell clones by anti-CD3 resulted in significant changes in transcripts critical for the recruitment and maturation of myeloid dendritic cells (DC) (e.g. GM-CSF, IL-4, TNF-a, MIP-1a, MIP-1a). Consistent with this prediction, human myeloid DC were efficiently matured in vitro by stimulation with these proteins, and these DC strongly activated human CD1d-restricted T cells. Furthermore, analysis of clones derived from the diabetic twin revealed marked defects in CD1d-restricted T cell function. Thus, associating both dysfunction and diminished frequency of CD1d-restricted T cells with the development of type 1 diabetes in humans.

To test this hypothesis, a CD1d (-/-) genotype was introgressed into the Non Obese Diabetic (NOD) mouse, the murine model of autoimmune diabetes. Notably, the in vivo modulation of CD1d-restricted T cells with the activating glycolipid ligand a-galactosylceramide (a-GalCer) presented by CD1d, or their deletion by the introgression of a CD1d-null phenotype, had significant impact on the course of diabetes development. Treatment of diabetes prone NOD mice with a-GalCer protected them from diabetes and resulted in the significant migration of myeloid DC to the draining pancreatic lymph node. Importantly, transfer of myeloid DC isolated specifically from the pancreatic lymph node completely protected NOD female mice from diabetes on transfer whilst those isolated from inguinal lymph nodes were ineffective. Therefore, activation of CD1d-restricted T cells results in significant cross talk between these cells and DC, resulting in modulation of DC function and in NOD mice, protection from autoimmunity.

References:

1. Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Balk SP, Strominger JL, Hafler DA. Extreme Th1 bias of regulatory VaJaQ T-cells in type 1 diabetes. Nature, 391:177-181, 1998.

2. Kent, S.C., Hafler, D.A., Strominger, J.L., Wilson, S.B. Noncanonical VaJaQ T cells with conservative alpha chain CDR3 region amino acid substitutions are restricted by CD1d. Human Immunol. 60: 1080-1089, 1999.

3. Wilson, S.B., Horton, H., Kent, S.C., Hafler, D.A., Strominger, J.L., & M. Byrne. The transcriptional profile of VaJaQ T cells. PNAS 97(13):7411-7416, 2000.

4. Kitchens, W. H., Byrne, M. C., Strominger, J.L., & S.B.Wilson. Using DNA chips to unravel the genetics of Type 1 diabetes. Diabetes Therapy and Treatment 2(2):249-258, 2000.

5. Yang O, Racke FR, Phuong Thi Nguyen, Gausling R, Severino ME, Horton HF, Byrne MC, Strominger JL, and Wilson SB. CD1d on Myeloid Dendritic Cells Stimulates Cytokine Secretion From and Cytolytic Activity of VaJaQ T Cells: A Feedback Mechanism for Immune Regulation. J.Immunol. 165(7):3756-3762, 2000.

6. Shi F-D, FlodstrÖm M, Balasa B, Kim SH, Van Gunst K, Strominger JL, Wilson SB, and Sarvetnick N. Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc. Nat. Acad. Sci. USA 98(25): 6777-6782, 2001.

7. Wilson SB and Byrne MC. Gene expression in NK T cells: Defining a functionally distinct CD1d-restricted T cell subset. Curr. Opin. Immunol.13: 555-561, 2001.

8. Naumov Y, Bahjat K, Gausling R, Abraham R, Exley MA, Balk SB, David C, Strominger JL, Clare-Salzer M, and Wilson SB. Activation of CD 1d- restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets.PNAS 98(24) 13838-13843, 2001.

9. Racke FK, Clare-Salzer M, and Wilson SB. Control of Myeloid Dendritic Cell Differentiation and Function by CD1d-restricted (NK) T cells. Frontiers in Bioscience 2002 April; 7:978-985.

10. Strominger JL,. Byrne MC, and Wilson SB. Regulation of dendritic Cell subsets by Va24JaQT cells (NKT cells) as revealed by transcriptional profiling. Transcriptome (In press).

11. Gillessen S, Namov YN, Nieuwenhuis EES, Exley MA, Lee, FS, Mach N, Luster AD, Richard S, Blumberg RS, Taniguchi M, Balk SP, Strominger JL, Dranoff G, and Wilson SB. CD1d-Restricted T Cells Regulate Dendritic Cell Function and Anti-tumor Immunity in a GM-CSF-Dependent Fashion. PNAS. USA 2003 Jul 22;100(15):8874-9.

12. Hou Runhua, Goloubeva O, Neuberg DS, Strominger JL, and Wilson SB. Interleukin-and interlukin-2 induced invariant NK T cell cytokine secretion and perforin expression independent of TCR activation. Immunol. 2003;110:30-713.

13. Strominger JL, Byrne MC, Wilson SB. Regulation of dendritic cell subsets by NKT cells. C R Biol. 2003;326:1045-8.

14. Bollyky PL, Wilson SB. CD1d-restricted T-cell subsets and dendritic cell function in autoimmunity. Immunol Cell Biol. 2004;82:307-14.






			Brian Wilson, MD, Ph.D. Control of Peripheral Tolerance by CD1d-restricted T Cells CD1d-restricted T cells (or “NKT cells”) have been reported to regulate an extremely diverse set of immunologic responses and diseases. Dysfunction of these T cells is clearly correlated with the development of autoimmunity, and in particular autoimmune diabetes. Despite the importance of CD1d-restricted T cells in this disease, how these T cells function normally and the exact nature of the disease-associated defects are unclear. While the field has focused largely on establishing functional roles for CD1d-restricted T cells in disease on a gene by gene basis, we approached this problem by using high-density oligonucleotide arrays to study CD1d-restricted clones isolated from monozygotic twin pairs discordant for type 1 diabetes. The use these of arrays was based on the hypothesis that an identification of the gene classes activated in a particular cell type would likely predict the function of that cell and potentially identify disease-related dysfunction in key regulatory circuits. When examined on the DNA microarrays, activation of CD1d-restricted T cell clones by anti-CD3 resulted in significant changes in transcripts critical for the recruitment and maturation of myeloid dendritic cells (DC) (e.g. GM-CSF, IL-4, TNF-a, MIP-1a, MIP-1a). Consistent with this prediction, human myeloid DC were efficiently matured in vitro by stimulation with these proteins, and these DC strongly activated human CD1d-restricted T cells. Furthermore, analysis of clones derived from the diabetic twin revealed marked defects in CD1d-restricted T cell function. Thus, associating both dysfunction and diminished frequency of CD1d-restricted T cells with the development of type 1 diabetes in humans. To test this hypothesis, a CD1d (-/-) genotype was introgressed into the Non Obese Diabetic (NOD) mouse, the murine model of autoimmune diabetes. Notably, the in vivo modulation of CD1d-restricted T cells with the activating glycolipid ligand a-galactosylceramide (a-GalCer) presented by CD1d, or their deletion by the introgression of a CD1d-null phenotype, had significant impact on the course of diabetes development. Treatment of diabetes prone NOD mice with a-GalCer protected them from diabetes and resulted in the significant migration of myeloid DC to the draining pancreatic lymph node. Importantly, transfer of myeloid DC isolated specifically from the pancreatic lymph node completely protected NOD female mice from diabetes on transfer whilst those isolated from inguinal lymph nodes were ineffective. Therefore, activation of CD1d-restricted T cells results in significant cross talk between these cells and DC, resulting in modulation of DC function and in NOD mice, protection from autoimmunity. References: 1. Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Balk SP, Strominger JL, Hafler DA. Extreme Th1 bias of regulatory VaJaQ T-cells in type 1 diabetes. Nature, 391:177-181, 1998. 2. Kent, S.C., Hafler, D.A., Strominger, J.L., Wilson, S.B. Noncanonical VaJaQ T cells with conservative alpha chain CDR3 region amino acid substitutions are restricted by CD1d. Human Immunol. 60: 1080-1089, 1999. 3. Wilson, S.B., Horton, H., Kent, S.C., Hafler, D.A., Strominger, J.L., & M. Byrne. The transcriptional profile of VaJaQ T cells. PNAS 97(13):7411-7416, 2000. 4. Kitchens, W. H., Byrne, M. C., Strominger, J.L., & S.B.Wilson. Using DNA chips to unravel the genetics of Type 1 diabetes. Diabetes Therapy and Treatment 2(2):249-258, 2000. 5. Yang O, Racke FR, Phuong Thi Nguyen, Gausling R, Severino ME, Horton HF, Byrne MC, Strominger JL, and Wilson SB. CD1d on Myeloid Dendritic Cells Stimulates Cytokine Secretion From and Cytolytic Activity of VaJaQ T Cells: A Feedback Mechanism for Immune Regulation. J.Immunol. 165(7):3756-3762, 2000. 6. Shi F-D, FlodstrÖm M, Balasa B, Kim SH, Van Gunst K, Strominger JL, Wilson SB, and Sarvetnick N. Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc. Nat. Acad. Sci. USA 98(25): 6777-6782, 2001. 7. Wilson SB and Byrne MC. Gene expression in NK T cells: Defining a functionally distinct CD1d-restricted T cell subset. Curr. Opin. Immunol.13: 555-561, 2001. 8. Naumov Y, Bahjat K, Gausling R, Abraham R, Exley MA, Balk SB, David C, Strominger JL, Clare-Salzer M, and Wilson SB. Activation of CD 1d- restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets.PNAS 98(24) 13838-13843, 2001. 9. Racke FK, Clare-Salzer M, and Wilson SB. Control of Myeloid Dendritic Cell Differentiation and Function by CD1d-restricted (NK) T cells. Frontiers in Bioscience 2002 April; 7:978-985. 10. Strominger JL,. Byrne MC, and Wilson SB. Regulation of dendritic Cell subsets by Va24JaQT cells (NKT cells) as revealed by transcriptional profiling. Transcriptome (In press). 11. Gillessen S, Namov YN, Nieuwenhuis EES, Exley MA, Lee, FS, Mach N, Luster AD, Richard S, Blumberg RS, Taniguchi M, Balk SP, Strominger JL, Dranoff G, and Wilson SB. CD1d-Restricted T Cells Regulate Dendritic Cell Function and Anti-tumor Immunity in a GM-CSF-Dependent Fashion. PNAS. USA 2003 Jul 22;100(15):8874-9. 12. Hou Runhua, Goloubeva O, Neuberg DS, Strominger JL, and Wilson SB. Interleukin-and interlukin-2 induced invariant NK T cell cytokine secretion and perforin expression independent of TCR activation. Immunol. 2003;110:30-713. 13. Strominger JL, Byrne MC, Wilson SB. Regulation of dendritic cell subsets by NKT cells. C R Biol. 2003;326:1045-8. 14. Bollyky PL, Wilson SB. CD1d-restricted T-cell subsets and dendritic cell function in autoimmunity. Immunol Cell Biol. 2004;82:307-14.