MHC-dependent desensitization of intrinsic anti-self reactivity.
The survival of naive T cells is compromised in the absence of molecules encoded by the major histocompatibility complex (MHC) while antigen-experienced T cells survive. We hypothesized that survival pressures in an in vivo, MHC-deficient environment would permit enrichment of less frequent antigen-experienced autoreactive cells at the expense of the majority of antigen naive T cells. To test this hypothesis, we generated MHC class I- and class II-deficient mice in NOD and C57Bl/6 (B6) backgrounds, and examined the capacity of adoptively transferred autoimmune-prone NOD T cells, or non-autoimmune prone naive B6 T cells, respectively, to reject transplanted wild-type pancreatic islets or transplantable tumors in the MHC-deficient mice. In the MHC-deficient environment, CD4 T cells acquired self-hostile properties (islet rejection and tumor invasion) that were independent from their genetic propensity for autoreactivity, while CD8 T cells required appropriate prior exposure to antigen in order to survive and function (reject tumor) in this environment; however, disengagement of Tob1, a negative regulator of proliferation, led to a reverse phenotype with regard to persistence of CD4 and CD8 T cells in the MHC-deficient environment. Our data suggest that self-peptide/MHC interactions have dual roles to facilitate survival and restrain autoreactivity, thus acting as integral components of an intrinsic network of negative regulation that maintains tolerance.
Jubala
Cristan M
CM
University of Colorado Cancer Center, Aurora, CO, USA.
Lamerato-Kozicki
Angela R
AR
Borakove
Michelle
M
Lang
Julie
J
Gardner
Lori A
LA
Coffey
David
D
Helm
Karen M
KM
Schaack
Jerome
J
Baier
Monika
M
Cutter
Gary R
GR
Bellgrau
Donald
D
Modiano
Jaime F
JF
D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003888:Desensitization, Immunologic; D007108:Immune Tolerance; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490903:Tob1 protein, mouse