Background/Purpose: Peripheral helper T (Tph) and follicular helper T (Tfh) cells are known to play a central role in the interaction between T and B cells, as well as in the mechanism of antibody production, indicating their potential importance in autoimmune diseases. Additionally, there have been reports demonstrating that Tph cells can directly cause tissue damage through the production of cytotoxic factors. However, our understanding of the physiology of Tph/Tfh cells, crucial for developing therapeutic drugs for autoimmune diseases, remains limited. The properties and differentiation mechanisms of Tph/Tfh cells differ between humans and mice, posing challenges for investigating their physiological roles, especially in vivo. To address this, it is essential to establish a method for replicating human Tph/Tfh cells in mice. In this study, we unexpectedly observed a significant proliferation of human Tph/Tfh and B cells in the spleens of immuno-deficient mice after transferring CD8T cells-depleted PBMCs. This led us to explore the potential use of these cells as a tool for studying human Tph/Tfh cells in mice and as a model for autoimmune disease.

Methods: We created humanized mice by transferring human peripheral blood mononuclear cells (PBMC; 1×10⁷ cells/mouse, hPBMC mice) or CD8T cells-depleted human PBMC (1×10⁷ cells/mouse, CD8T⊿hPBMC mice) to immune-deficient (NSG) mice. We compared the effects of graft versus host disease (GVHD) between hPBMC mice and CD8T⊿hPBMC mice. Additionally, we used flow cytometry to examine the immunological phenotype of CD8T⊿hPBMC mice.

Results: GVHD resulting from the transfer of PBMC to immune-deficient mice was significantly reduced in CD8T⊿PBMC mice, which could be used without GVHD symptoms for at least 30 days. Subsequently, we observed a notable increase in a Tph-like subset (CD4+PD-1+CXCR5- cells), a Tfh-like subset (CD4+PD-1+CXCR5- cells), and B cells in the spleens of CD8T⊿PBMC mice compared to hPBMC mice. These Tph and Tfh-like subsets of CD8T⊿PBMC mice expressed IL-21/CXCL13, functional molecules of these cells. We also investigated the presence of CXCL13+Tph cells in systemic organs of CD8T⊿PBMC mice and found that these cells infiltrated organs exhibiting symptoms similar to those of Sjogren’s syndrome (SjS), such as salivary glands (SGs), lungs, and kidneys. Our analysis of single-cell RNA sequencing of human immune cells infiltrating the SGs revealed a significant infiltration of CXCL13+IL-21+Tph cells, accompanied by a marked decrease in saliva volume as observed in SjS. These findings suggest that these cells may induce Sjogren’s-like symptoms through damage to the SGs. Finally, we examined the effects of administering IL-12/TGF-β1/IFN-α, known to induce Tph/Tfh cells, on salivary gland symptoms in CD8T⊿PBMC mice. This resulted in the activation of Tph cells and exacerbation of symptoms in the SGs, indicating the potential importance of Tph cell activation in the pathogenesis of this model.

Conclusion: This study demonstrated that PBMC-derived human Tph/Tfh and B cells can proliferate in vivo without GVHD symptoms by transferring CD8T cells-depleted human PBMC, leading to the development of SjS-like pathology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd8t-cells-depletion-promotes-human-tph-tfh-cells-proliferation-and-sjogren-syndrome-like-symptoms-without-graft-versus-host-diseases-in-pbmc-transferred-humanized-mice/