Targeting the pMHC–TCR Interaction: Molecular Strategies and Therapeutic Potential in Autoimmunity

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides a timely and conceptually focused overview of antigen-specific immunomodulation in autoimmune diseases, centering on the pMHC–TCR interaction. The manuscript highlights important mechanistic aspects, including structural determinants of pMHC–TCR recognition and factors contributing to tolerance breakdown, and discusses emerging therapeutic strategies such as pMHC-based approaches and CAR-Treg therapies. The topic is of broad interest, and the emphasis on precision immunotherapy represents a valuable perspective. However, several aspects require further clarification and refinement to improve the manuscript.

 

The manuscript positions the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. While this is a reasonable perspective, it may oversimplify the complexity of immune regulation. Additional discussion is needed to better contextualize this axis relative to other key immune checkpoints (e.g., co-stimulatory/inhibitory receptors such as CD28, CTLA-4, PD-1, and Siglecs). This would strengthen the conceptual rigor and avoid overstatement.

 

The authors should ensure that key principles are sufficiently discussed and linked to therapeutic design. For example, In Figure 4, the specific mechanics of tolDC appear unclear and should be further clarified or revised.

 

While multiple strategies are mentioned (e.g., pMHC-decorated nanoparticles, soluble pMHC, CAR-Treg), the discussion appears largely descriptive. A more critical evaluation is needed, including the comparative advantages and limitations of each approach, as well as translational barriers?

 

Ensure consistent use of terminology (e.g., “auto tolerance” should be standardized to “self-tolerance” or “immune tolerance”)

 

The capitalization of words in figure captions should checked and standardized for consistency

Author Response

• The manuscript positions the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. While this is a reasonable perspective, it may oversimplify the complexity of immune regulation. Additional discussion is needed to better contextualize this axis relative to other key immune checkpoints (e.g., co-stimulatory/inhibitory receptors such as CD28, CTLA-4, PD-1, and Siglecs). This would strengthen the conceptual rigor and avoid overstatement.

 

We fully agree with the Reviewer’s insightful assessment. While the pMHC–TCR interaction is the primary "Signal 1" for T-cell activation, we recognize that the physiological initiation of an autoimmune response is far more nuanced. In the revised manuscript, we have addressed this by expanding Section 2.3,page 5, lane 221 and by addition of 5 references (52-56) . We have added a new paragraph highlighting the importance of PD-1 and  Siglecs as key inhibitory rheostats that dampen autoreactive signals at the immunological synapse.

 

• The authors should ensure that key principles are sufficiently discussed and linked to therapeutic design. For example, In Figure 4, the specific mechanics of tolDC appear unclear and should be further clarified.

 

We appreciate the Reviewer’s suggestion to clarify the functional state of tolDCs. In the revised manuscript, we have added a dedicated paragraph in Section 3.4, page 15, lane 617 to describe the molecular signature of tolDCs. Specifically, we highlight that presentation of autoantigens via MHC class II occurs under conditions of minimal CD80/CD86 co-stimulation and an anti-inflammatory cytokine milieu (IL-10/TGF-β/IL-27). We have also updated Figure 4 to explicitly reflect the down-regulation of CD80/86, which is crucial for delivering a sub-immunogenic TCR signal and driving the differentiation of FoxP3⁺ and Tr1 regulatory T cells.

 

• While multiple strategies are mentioned (e.g., pMHC-decorated nanoparticles, soluble pMHC, CAR-Treg), the discussion appears largely descriptive. A more critical evaluation is needed, including the comparative advantages and limitations of each approach, as well as translational barriers?

We thank the Reviewer for this constructive critique. We agree that a comparative analysis of therapeutic platforms is essential. According to reviewer suggestion we added discussion and comparison of different therapeutic strategies in each section:  Section 3.1, page 10, line 481; Section 3.2, page 12, line 548; Section 3.3, page 13, line 587; Section 3.4, page 15, line 625; Section 4, page 19, line 699; Section 5.1, page 23, line 773; Section 5.3, page 24, line 801

 

• Ensure consistent use of terminology (e.g., “auto tolerance” should be standardized to “self-tolerance” or “immune tolerance”)

 

We thank the Reviewer for pointing out these terminological inconsistencies. We have conducted a comprehensive review of the entire manuscript to ensure that scientific terms are used consistently and adhere to the established immunological nomenclature. Specifically: change auto tolerance into self – tolerance in abstract section page 1 line 23.

Reviewer 2 Report

Comments and Suggestions for Authors

Nechaeva et al. provide in this review a comprehensive overview about the interaction of pMHC-TCR and the molecular strategies and studies which are currently conducted in order to find new ways to treat autoimmunity. The paper is somehow a small version of an “immunology textbook” since the topic is indeed extremely complex and touches many aspects of immunology. Many similar reviews have been published in the last years dealing with new cellular and molecular approaches to target and treat various autoimmune diseases. Yet, this is on the one hand indicative for the importance of the field and the need to continuously improve our treatment options for the patients. Thus, it is essential for the scientific community to have access to recent overview articles summarizing the current knowledge about this – highly complex- topic.

 

The manuscript is well written and easy to understand although the topic has enormous dimensions and includes a large amount of information and studies.

 

Two major points of criticism emerged during the review process:

 

1. The authors use 124 References for the paper. Such an amount is necessary for such an extensive topic and paper. Yet, there are many paragraphs where citations are missing. So, it is sometimes not clear if the authors present us their own point of view or if these statements are based on results published in scientific papers.

 

2. In my opinion an important aspect is missing the section about CAR-T cells against autoimmunity. The concept of creating CAR-T cells against the TCR, i.e. against TRBC1+ or TRBC2+ T cells or against g/d T cells, was established by Paul Maciocia and colleagues and is today an interesting and (hopefully) promising strategy for cancer therapy but in the future maybe also for autoimmune diseases.

 

Author Response

• The authors use 124 References for the paper. Such an amount is necessary for such an extensive topic and paper. Yet, there are many paragraphs where citations are missing. So, it is sometimes not clear if the authors present us their own point of view or if these statements are based on results published in scientific papers.

 

We sincerely thank the Reviewer for this observation. We have carefully re-examined the entire manuscript to ensure that every factual claim, mechanistic description, and clinical data point is appropriately cited.

We have added 43 new citations in sections where the supporting evidence was previously implied but not explicitly referenced.The total number of references has been updated to 167 to reflect these additions.

 

• In my opinion an important aspect is missing the section about CAR-T cells against autoimmunity. The concept of creating CAR-T cells against the TCR, i.e. against TRBC1+ or TRBC2+ T cells or against g/d T cells, was established by Paul Maciocia and colleagues and is today an interesting and (hopefully) promising strategy for cancer therapy but in the future maybe also for autoimmune diseases.

 

We are grateful to the Reviewer for highlighting this approach. We agree that the work of Maciocia et al. regarding TRBC1/TRBC2-targeted CAR-T cells represents a paradigm shift that could extend far beyond T-cell malignancies into the realm of precision medicine for autoimmunity. In the revised manuscript, we have added a new paragraph, describing this approach in Section 5.1, page 22, line 722 . We also have added three new references [152-154 ], reflecting these recent developments.

Reviewer 3 Report

Comments and Suggestions for Authors

In this manuscript, Alina M Nechaeva et al. provide an overview of antigen-specific immunotherapeutic strategies targeting the pMHC–TCR interaction in autoimmune diseases. The authors successfully combine fundamental immunological concepts with emerging therapeutic strategies, offering a clear and informative perspective on the current state of the field.

The manuscript is largely descriptive. While it summarizes many approaches (e.g., soluble pMHC, nanoparticles, tolDCs), it lacks sufficient critical comparison between strategies.

The authors should better highlight:Advantages vs limitations of each platform

A clearer distinction between preclinical, early clinical, and approved therapies is needed.

Sections on T-cell activation, tolerance, and subsets (Section 2.2–2.3) are very detailed but partially redundant for a review focused on therapeutic targeting. Consider condensing these sections and focusing more on aspects directly relevant to pMHC-targeted interventions.

The authors may strengthen the manuscript by considering recent literature on β2GPI-related antigenic complexes and downstream signaling pathways in APS. In particular, studies addressing β2GPI/PF4 complexes of january 2026, post-translational modifications generating neoepitopes such as carbamylation of β2GPI,  and extracellular vesicle-mediated antigen presentation would significantly enhance the translational relevance of the review

Author Response

• The manuscript is largely descriptive. While it summarizes many approaches (e.g., soluble pMHC, nanoparticles, tolDCs), it lacks sufficient critical comparison between strategies. The authors should better highlight: Advantages vs limitations of each platform.

 

We fully acknowledge this important point, which was also highlighted by Reviewer #1. We agree that a critical evaluation is essential for moving the manuscript from a descriptive overview to a high-level analytical review. To move beyond a descriptive narrative, we have added a comparative discussion of different strategies in each section, describing the therapeutic strategies: Section 3.1, page 10, line 481; Section 3.2, page 12, line 548; Section 3.3, page 13, line 587; Section 3.4, page 15, line 625; Section 4, page 19, line 699; Section 5.1, page 23, line 773; Section 5.3, page 24, line 801

• A clearer distinction between preclinical, early clinical, and approved therapies is needed.

 

We entirely agree with the Reviewer’s assessment. To address this, we have implemented the following changes, particularly in Section 3.1 (Soluble Antigen Immunotherapy):  We have revised the discussion of free antigen therapies to clearly distinguish between those in early-stage discovery and those that have reached Phase II/III clinical trials  - Section 3.1, page 10, line 448. We have also created a new Table 1, titled " Immunotherapeutic Agents Based on soluble antigens ". This table systematically categorizes the approaches discussed in this section.

 

• Sections on T-cell activation, tolerance, and subsets (Section 2.2–2.3) are very detailed but partially redundant for a review focused on therapeutic targeting. Consider condensing these sections and focusing more on aspects directly relevant to pMHC-targeted interventions.

 

We appreciate the Reviewer’s guidance on the manuscript's focus. We have significantly condensed Sections 2.2 and 2.3 to eliminate redundant information and improve the paper's overall flow. Specifically, we have removed detailed descriptions of the effector mechanisms of CD8+ Cytotoxic T Lymphocytes (CTLs), such as the pathways of target cell apoptosis page 4, line 146 ; have removed detailed descriptions of T-cell effector subsets and their respective cytokine profiles (e.g., specific pathways of Th-cell polarization) page 4, line 149 and line 152; have removed the repetitive characterization of DCs as professional antigen-presenting cells -  page 5, line 214.

 

• The authors may strengthen the manuscript by considering recent literature on β2GPI-related antigenic complexes and downstream signaling pathways in APS. In particular, studies addressing β2GPI/PF4 complexes of january 2026, post-translational modifications generating neoepitopes such as carbamylation of β2GPI and extracellular vesicle-mediated antigen presentation would significantly enhance the translational relevance of the review

 

We are grateful to the Reviewer for pointing us toward these recent and highly relevant developments. We agree that the molecular landscape of APS provides a perfect example of how neoepitopes and complex formation dictate pMHC-TCR interactions. In the revised manuscript, we have added a new paragraph , discussing this subject  Section 2.5, page 7, line 360 and 4 new references (73,75,76,77)

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have completed my requests