Image-guided analyses reveal that non-CD4 splenocytes contribute to CD4+ T cell-mediated inflammation leading to islet destruction by altering their local function and not systemic trafficking patterns.
Recruitment of CD4(+) T cells into islets is a critical component of islet inflammation (insulitis) leading to type 1 diabetes; therefore, determining if conditions used to treat diabetes change their trafficking patterns is relevant to the outcome. Cotransfer of CD4(+)BDC2.5 (BDC) cells with non-CD4 splenocytes obtained from newly diabetic NOD mice, but not when they are transferred alone, induces accelerated diabetes. It is unclear whether these splenocytes affect diabetes development by altering the systemic and/or local trafficking and proliferation patterns of BDC cells in target and nontarget tissues. To address these questions, we developed an animal model to visualize BDC cell trafficking and proliferation using whole-body in vivo bioluminescence imaging and used the images to direct tissue sampling for further analyses of the cell distribution within tissues. The whole-body, or macroscopic, trafficking patterns were not dramatically altered in both groups of recipient mice. However, the local patterns of cell distribution were distinct, which led to invasive insulitis only in cotransferred mice with an increased number of islet-infiltrating CD11b(+) and CD11c(+) cells. Taken together, the non-CD4 splenocytes act locally by promoting invasive insulitis without altering the systemic trafficking patterns or proliferation of BDC cells and thus contributing to diabetes by altering the localization within the tissue.
Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Mi-Heon
MH
Lee
Wen-Hui
WH
Lee
Yanghao
Y
Van
Christopher H
CH
Contag
Chih-Pin
CP
Liu
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000276:immunology; D002465:Cell Movement / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology; D005434:Flow Cytometry; D007091:Image Processing, Computer-Assisted; D007515:Islets of Langerhans / Q000473:pathology* / Q000503:physiopathology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010195:Pancreatitis / Q000150:complications / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D013154:Spleen / Q000166:cytology* / Q000378:metabolism
D015704:CD4 Antigens; D008164:Luminescent Proteins; D008156:Luciferases