Occult CD45 T cell developmental defect in type 1 diabetes

Individuals with insulin-dependent diabetes mellitus, as well as high-risk prediabetic subjects who are identified prior to the onset of hyperglycaemia by abnormal autoantibodies to both insulin and islet cells have an autologous antigen presenting cell (APC) defect that results in sluggish T cell proliferation in the in vitro autologous mixed lymphocyte reaction (AMLR). In contrast, lower-risk relatives, who produce autoantibodies restricted to insulin and fail to develop overt hyperglycaemia, show apparently normal autologous antigen presenting cell function and paradoxically demonstrate excessive T cell proliferation in the AMLR. We have now characterized this lower-risk vigorous T cell response in the autologous mixed by lymphocyte reaction as a predominant and excessive proliferation of CD4+ T cells to self-antigens (n = 10, p < 0.001). In addition, the normal autologously driven transition of the expanding CD45RA+ subset of CD4+ cells into transient CD45RA+RO+ cells with subsequent progression to CD45RA-RO+ cells is partially blocked in the lower-risk autologous response compared to controls (n = 5, p = 0.01, respectively). Autologously driven T cell developmental transitions also appear to be blocked in these individuals in vitro; the peripheral blood of lower-risk relatives contains an increased number of CD4+ cells abnormally coexpressing CD45RA and CD45RO (p = 0.01). Interestingly, in two twin sets reconstitution of T cells from the diabetic twin of an identical twin-pair that is discordant for Type 1 diabetes with the APCs of the nondiabetic twin resulted in overly vigorous T cell proliferation dominated by CD4+ cells; phenotypically, these CD4+ cells at the end of the reaction were similar to those of lower-risk relatives in that the CD45RA+RO+ transition into CD45RA-RO+ cells was now observed to be defective. Therefore, T cells from lower-risk relatives and individuals with Type 1 diabetes appear to possess similar intrinsic T cell developmental defects in CD45 transitions that are apparent after normal autologous antigen stimulation.