แนวคิดหลัก
Heightened self-reactivity of CD8+ T cells during thymic positive selection, as indicated by increased CD5 expression, predisposes them to an effector/memory-like phenotype and enhanced diabetogenic potential in non-obese diabetic (NOD) mice.
บทคัดย่อ
This study investigates the influence of thymic positive selection on the development of diabetogenic CD8+ T cells in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). The authors demonstrate that naïve CD8+ T cells from NOD mice can be stratified based on their CD5 expression, which serves as a surrogate marker for T cell receptor (TCR) self-reactivity during thymic selection.
Key findings:
Naïve CD8+ T cells with higher CD5 expression (CD5hi) exhibit a more differentiated/memory-like phenotype, with increased activation, proliferation, and effector molecule expression compared to their CD5lo counterparts.
Transcriptomic analysis reveals that CD5hi CD8+ T cells have a gene expression profile associated with T cell activation, effector function, and autoimmune disease pathways, such as type 1 diabetes and inflammatory bowel disease.
In an adoptive transfer experiment, CD5hi CD8+ T cells induce more severe insulitis and accelerated diabetes onset in NOD Rag1-/- recipient mice compared to CD5lo CD8+ T cells.
The heightened self-reactivity of CD8+ T cells in NOD8.3 transgenic mice, which express a diabetogenic TCR, overrides the protective effects of transgenic phosphatase Pep expression, which normally attenuates TCR signaling and diabetes incidence in NOD mice.
TCR repertoire analysis reveals increased utilization of specific TRAV, TRAJ, TRBV, and TRBJ gene segments in the CD5hi CD8+ T cell population, suggesting a link between self-reactivity and autoimmune disease-associated clonotypes.
Overall, the data indicate that the degree of self-reactivity acquired during thymic positive selection shapes the pathogenic potential of autoantigen-specific CD8+ T cells in autoimmune diabetes.
สถิติ
The CD5hi CD8+ T cells from NOD mice exhibit higher levels of p-CD3ζ and p-Erk compared to CD5lo CD8+ T cells.
The CD5hi CD8+ T cells from NOD mice have increased expression of T-bet, Eomes, Granzyme B, TNF-α, IFN-γ, and IL-2 compared to CD5lo CD8+ T cells.
The CD5hi CD8+ T cell-transferred group in NOD Rag1-/- mice showed earlier diabetes onset and more severe insulitis compared to the CD5lo CD8+ T cell-transferred group.
The transgenic Pep expression failed to attenuate the diabetogenic potential of CD8+ T cells in NOD8.3 mice, which have intrinsically high CD5 expression.
คำพูด
"CD5hiCD8+ clones may be potential targets for autoimmune diabetes treatment."
"Exploring a potential modulation of CD5-dependent TCR basal signaling and its impact on T cell reactivity may offer a promising therapeutic strategy for the treatment of T1D in the future."