The primacy of CD8 T lymphocytes in type 1 diabetes and implications for therapies.
Type I diabetes (TID) is an autoimmune disease in which insulin-secreting beta cells of the pancreatic islets are destroyed by T lymphocytes. Until the 1990s, the prevailing dogma was that the attack was attributable to rogue T lymphocytes bearing CD4 markers on their surface (CD4 T helper lymphocytes). Today, the prevailing view is that rogue T cells bearing CD8 markers or cytotoxic CD8 T lymphocytes are also important and perhaps the foremost contributors to beta-cell death. Recognizing CD8 T-cell subsets as the prime culprits has helped to trace the disease's pathogenesis to abnormal T-cell education. Defective education can occur when antigen-presenting cells fail to assemble and present self-antigens to naïve T cells. The failure in that process, normally designed to prevent T cells' attack on the body's own antigens, enables self-reactive T cells to escape into the circulation. Once released, the self-reactive CD8 T cells kill specific self-antigens, which, in the case of TID, include insulin and other key proteins associated with beta cell functions. Abnormalities during T-cell education have been mapped in part to genetic defects in specific gene-encoding regions of the major histocompatibility complex class I region and to proteins that assemble self-peptides into the MHC class I structure that map within the MHC class II region. Two decades of research have led to understanding of genetic and functional defects in the immune system, placing us at the threshold of finding new therapeutic strategies aimed at eliminating autoreactive CD8 T cells, while preserving healthy immune cells.
Faustman
Denise L
DL
Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. faustman@helix.mgh.harvard.edu
Davis
Miriam
M
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD
N Engl J Med. 1993 Sep 30;329(14):977-86
8366922
J Clin Invest. 1993 May;91(5):2301-7
8486790
J Clin Invest. 2001 Jul;108(1):63-72
11435458
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13644-9
18755894
Science. 2003 Nov 14;302(5648):1223-7
14615542
Tissue Antigens. 2003 Feb;61(2):146-53
12694582
Adv Immunol. 2008;100:1-12
19111161
J Immunol. 2003 Jan 1;170(1):620-7
12496451
Tissue Antigens. 1997 Dec;50(6):576-85
9458110
Genet Epidemiol. 1995;12(5):441-53
8557177
Cell. 1985 Sep;42(2):457-67
2411422
Science. 1991 Dec 20;254(5039):1756-61
1763324
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11032-6
1763019
Diabetes Care. 2005 Oct;28(10):2384-7
16186267
Nature. 1991 Sep 26;353(6342):326-9
1922338
J Immunol. 1999 Jan 15;162(2):852-9
9916708
Diabetes. 2007 Jan;56(1):270-5
17192492
Ann Rheum Dis. 2006 Aug;65(8):1021-7
16414974
J Immunol. 1997 Sep 15;159(6):3068-80
9300732
Hum Immunol. 1997 Apr 1;53(2):159-66
9129974
Diabetes. 1988 Oct;37(10):1444-8
2458291
Nature. 1987 Oct 8-14;329(6139):506-12
3309677
Nat Med. 1999 Sep;5(9):1026-31
10470079
Nature. 1990 Nov 15;348(6298):213-6
1700303
Ann N Y Acad Sci. 1998 Apr 15;842:138-55
9599304
Hum Immunol. 2002 Aug;63(8):657-64
12121673
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11128-32
7972022
Diabetes. 1993 Jan;42(1):44-55
8093606
Eur J Immunol. 1992 Sep;22(9):2387-93
1516628
J Immunol. 1989 Aug 15;143(4):1094-100
2787356
Nature. 1989 Dec 7;342(6250):692-6
2594067