Where CD4+CD25+ T reg cells impinge on autoimmune diabetes.
Foxp3 is required for the generation and activity of CD4(+)CD25(+) regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in the draining lymph nodes, nor accelerate the onset of T cell infiltration of the pancreatic islets. However, this insulitis was immediately destructive, causing a dramatic progression to overt diabetes. Microarray analysis revealed that T reg cells in the insulitic lesion adopted a gene expression program different from that in lymph nodes, whereas T reg cells in draining or irrelevant lymph nodes appeared very similar. Thus, T reg cells primarily impinge on autoimmune diabetes by reining in destructive T cells inside the islets, more than during the initial activation in the draining lymph nodes.
Chen
Zhibin
Z
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Herman
Ann E
AE
Matos
Michael
M
Mathis
Diane
D
Benoist
Christophe
C
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2