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.
University of Colorado Cancer Center, Aurora, CO, USA.
Cristan M
CM
Jubala
Angela R
AR
Lamerato-Kozicki
Michelle
M
Borakove
Julie
J
Lang
Lori A
LA
Gardner
David
D
Coffey
Karen M
KM
Helm
Jerome
J
Schaack
Monika
M
Baier
Gary R
GR
Cutter
Donald
D
Bellgrau
Jaime F
JF
Modiano
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