Distinct Thymic Self-Recognition Shapes the Pathogenicity of Autoantigen-Specific CD8+ T Cells in Non-Obese Diabetic Mice

Core Concepts

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.

Abstract

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.

Stats

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.

Quotes

"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."

Key Insights Distilled From

Thymic self-recognition-mediated TCR signal strength modulates antigen-specific CD8+ T cell pathogenicity in non-obese diabetic mice

by Ho,C.-L., Ye... at www.biorxiv.org 06-12-2024

https://www.biorxiv.org/content/10.1101/2024.06.10.596762v1

Deeper Inquiries

How do the distinct TCR repertoires of CD5hi and CD5lo CD8+ T cells contribute to their differential pathogenicity in autoimmune diabetes?

The distinct TCR repertoires of CD5hi and CD5lo CD8+ T cells play a crucial role in their differential pathogenicity in autoimmune diabetes. CD5hiCD8+ T cells, characterized by higher self-reactivity and TCR signal strength, exhibit a unique TCR repertoire with increased utilization of specific V and J gene families, such as TRAV13-2, TRAV16D-DV11, TRAV3-3, TRAJ32, TRBV14, TRBV16, TRBJ2-1, and TRBJ2-7. These TCR repertoires are associated with autoimmune disease-related clonotypes, suggesting a predisposition towards autoreactivity and enhanced responses to self-antigens. On the other hand, CD5loCD8+ T cells have a different TCR repertoire with lower utilization of certain gene families, indicating a lower self-reactivity and potentially reduced pathogenicity in autoimmune diabetes. The differential TCR repertoires between CD5hi and CD5lo CD8+ T cells contribute to their distinct effector functions, activation potential, and memory cell formation, ultimately influencing their pathogenicity in autoimmune diabetes.

How might the high self-reactivity of CD8+ T cells during thymic selection override the protective effects of transgenic phosphatase Pep expression in NOD8.3 mice?

The high self-reactivity of CD8+ T cells during thymic selection, as indicated by elevated CD5 expression and TCR signal strength, can override the protective effects of transgenic phosphatase Pep expression in NOD8.3 mice through several potential mechanisms:

Thymic Positive Selection: CD5 expression is proportional to T cell self-reactivity during thymic positive selection. Thymocytes with higher self-reactivity TCRs induce CD5 expression, which helps them adapt to strong TCR signaling and reduces the likelihood of negative selection. This process enriches the mature CD8+ T cell repertoire with clones that exhibit increased responses to self-peptide-MHC, leading to the generation of autoreactive T cells with enhanced effector functions.

TCR Signaling Strength: The intrinsic high CD5-linked self-reactivity in NOD8.3 CD8+ T cells results in elevated TCR signaling strength, which may override the downregulation of TCR signaling mediated by transgenic phosphatase Pep expression. This high TCR signaling strength in CD5hiCD8+ cells confers a predisposition towards autoreactivity and enhanced immune responses to self-antigens, negating the protective effects of transgenic Pep expression.

Effector Functions: CD5hiCD8+ cells with high self-reactivity exhibit a poised phenotype for effector T cells in autoimmune diseases, characterized by increased activation, proliferation, and cytokine production. These cells are more resistant to transgenic Pep-mediated attenuation of TCR signaling and effector functions, maintaining their diabetogenic susceptibility in NOD8.3 mice.

Could targeting the CD5-dependent TCR signaling pathway in CD8+ T cells be a viable therapeutic approach for type 1 diabetes, and how might this strategy be implemented?

Targeting the CD5-dependent TCR signaling pathway in CD8+ T cells could be a promising therapeutic approach for type 1 diabetes. By modulating the TCR signal strength and self-reactivity of CD8+ T cells, it may be possible to regulate their activation, proliferation, and effector functions, ultimately reducing autoimmune responses and preventing the destruction of pancreatic beta cells.
Implementation of this strategy could involve the development of targeted therapies that specifically inhibit CD5-mediated TCR signaling in CD8+ T cells. This could be achieved through the use of small molecule inhibitors, monoclonal antibodies, or gene editing techniques to modulate CD5 expression or function. By selectively targeting the CD5-dependent TCR signaling pathway, it may be possible to dampen the autoimmune response in type 1 diabetes while preserving normal immune function. Further research and clinical trials would be needed to validate the efficacy and safety of this approach in the treatment of type 1 diabetes.