Interleukin-21-dependent modulation of T cell antigen receptor reactivity towards low affinity peptide ligands in autoreactive CD8(+) T lymphocytes.
IL-21 promotes autoimmune type-1 diabetes (T1D) in NOD mice by facilitating CD4(+) T cell help to CD8(+) T cells. IL-21 also enables autoreactive CD8(+) T cells to respond to weak TCR ligands and induce T1D. Here, we assessed whether IL-21 is essential for T1D induction in a mouse model where the disease can occur independently of CD4 help. In this model, which expresses lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) antigen under the rat insulin promoter (RIP-GP), LCMV infection activates CD8(+) T cells reactive to the GP-derived GP33 peptide that attack pancreatic islets and cause T1D. We show that IL-21 deficiency in RIP-GP mice did not impair T1D induction by LCMV expressing the wildtype GP33 peptide. Surprisingly, LCMV-L6F, expressing a weak peptide mimic of GP33, induced T1D more efficiently in Il21(-/-)RIP-GP mice than in controls. However, LCMV-C4Y expressing a very weak peptide mimic of GP33 did not induce T1D in Il21(-/-) mice, but T cells from the infected mice caused disease in lymphopenic RIP-GP mice upon adoptive transfer. Using Nur77(GFP) reporter mice, we show that CD8(+) T cells from Il21(-/-) mice expressing the GP33-specific transgenic P14 TCR showed increased reactivity towards low affinity TCR ligands. Collectively, our findings show that IL-21 is not always required for T1D induction by autoreactive CD8(+) T cells, and suggest that IL-21 may play an important role in regulating CD8(+) T cell reactivity towards low affinity TCR ligands.
Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
Diwakar
D
Bobbala
Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
Sakina
S
Orkhis
Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
Rajani
R
Kandhi
Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada. Electronic address: Sheela.Ramanathan@USherbrooke.ca.
Sheela
S
Ramanathan
Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada. Electronic address: Subburaj.Ilangumaran@Usherbrooke.ca.
Subburaj
S
Ilangumaran
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000821:virology; D007328:Insulin / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000821:virology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count / Q000379:methods; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D000098546:Interleukin-21
D000956:Antigens, Viral; D007328:Insulin; D007378:Interleukins; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D000098546:Interleukin-21
Altered peptide ligand; Autoimmune diabetes; CD8(+) T cells; Interleukin-21; TCR