David Usharauli1/ 🧵 What is the TCR specificity of Foxp3+ Tregs? They're as diverse as conventional T cells, but very few antigen-specific Tregs have been described. This lack of specificity leads to many unfounded statements. Let's dive in. 🔬
2/ A common claim: Tregs are autoreactive, meaning they recognize self-antigens. Since Tregs protect against autoimmunity, this seems logical. But does it really hold up? 🤔 Let's run a thought experiment. 💭
3/ Here’s the undisputed evidence about Tregs:
1. Diverse TCR repertoire 🧬
2. Need TCR engagement in the periphery to stay active 🔄
3. Require IL-2 from other T cells 🔗
4. Inhibit other T cells in an antigen-specific manner ⚔️
5. Antigen-specific autoimmunity exists 🔍
4/ Based on this evidence, if Tregs inhibit other T cells in an antigen-specific manner, they must recognize similar antigens. Likewise, IL-2 supply from other T cells is also likely antigen-specific. 🔑
5/ But what antigens do Tregs and other T cells recognize to collaborate on IL-2 supply? Is it auto-antigen? Unlikely. Why? Because for autoimmunity to happen, Tregs would need to lose their functionality. ⚠️
6/ How can antigen-specific Tregs lose their functionality? By losing the antigen. Without the anchor antigen to engage the Treg TCR and collaborate with other T cells for IL-2, the process breaks down. 🔓
7/ But how could we lose a self-antigen? Not realistic. And if a self-antigen is lost, how can autoimmunity occur? No antigen, no autoimmunity. 🚫
8/ Could there be a self-antigen that keeps Tregs and IL-2+ T cells together while autoimmunity targets other self-antigens? Unlikely, as Treg inhibition is antigen-specific.
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#Immunology
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#Immunology
9/ If the lost anchor antigen is similar to the target self-antigen, Treg–IL-2+ T cell collaboration stays intact. 🔄 If they’re different, losing the anchor antigen shouldn’t affect other self-antigens. ⚖️ No disruption → No autoimmunity!
10/ So, antigen-specific autoimmunity can't happen under the prevailing Treg biology model. ❌ But then, how do antigen-specific autoimmune diseases occur? 🤔 Here’s the twist… 🔄
11/ The anchor antigen Tregs recognize may not be a self-antigen. It could be microbiota-derived, mimicking self — cross-reactive. 🌿🔄 Loss of specific microbiota providing these antigens could lead to antigen-specific autoimmunity.