Biology subjects

de Paiva, C. S.

Publications and source records attributed to de Paiva, C. S..

3 recordsLinked to original sources

bioRxiv2026

Mechanisms of CD4+ T tolerance to a corneal epithelial neoantigen

Tissue-specific peripheral tolerance mechanisms are essential to prevent autoimmunity. The cornea is immune privileged, and anterior chamber-associated immune deviation (ACAID) governs its inner surface. However, the mechanisms that apply to corneal epithelial (outer surface) antigens remain unknown. Using an inducible, cornea-restricted neoantigen mouse model, we found that the cornea relies on inducible regulatory T cells (Tregs) rather than ignorance or ACAID for its epithelial antigens. Although the cornea is both avascular and alymphatic, its epithelial antigens are still efficiently presented by ocular surface-derived antigen-presenting cells to T cells in draining lymph nodes under homeostatic conditions, leading to conventional antigen-specific Treg expansion without ocular pathology. This tolerance was not absolute: systemic immunization redirected antigen-specific responses toward pathogenic effector T cells that disrupted epithelial barrier function. These findings identify Treg induction as a dominant mechanism of corneal epithelial immune homeostasis and demonstrate that inflammatory priming can render a tolerated corneal antigen into an autoimmune target, providing mechanistic insight into dry eye pathogenesis. SummaryThis study shows that immune tolerance to corneal epithelial neoantigens relies not on immune privilege but on peripherally induced regulatory T cells in the draining lymph nodes that can be subverted by innate activation, shedding light on ocular surface disease pathophysiology.

immunology↗

bioRxiv2026

Autoimmune CD4+T cells Cause Meibomian Gland Dysfunction

Sjogren disease (SjD) is an autoimmune disease driven by autoreactive CD4+T cells that leads to an immune-mediated loss of lacrimal glands. Meibomian glands are lipid-producing glands in the eyelids that help prevent tear evaporation. While the role of T cells in lacrimal gland-mediated destruction is well established, it is unknown whether pathogenic T cells can cause MG dysfunction (MGD). Herein, we investigated whether autoreactive CD4+T cells induce MGD and characterized the pathophysiologic mechanisms using an adoptive transfer model. T cells were isolated from CD25KO (CD4KO) or wild-type (CD4WT) mice, transferred into Rag1KO mice. Further, CD4KO cells were co-adoptively transferred with WT regulatory T cells (CD4KO+TregsWT). Our results demonstrate that CD4KO recipients had MG dropout, CD4+IFN-{gamma}+ infiltration, increased MHC II presentation within the periglandular area, MG fibrosis, and decreased lipid production and upregulation of pathways related to inflammation, including Type II interferon signaling. Rag1KO, CD4WT, and CD4KO+TregsWT recipients exhibited minimal inflammation in the periglandular MG area. These results indicate that autoimmune CD4+T cells are sufficient to cause MGD, and healthy young regulatory T cells can prevent T-cell-mediated damage. Taken together, our findings provide mechanistic insights into the pathogenesis autoimmune SjD, and could impact how patients are managed in the clinic.

pathology↗

bioRxiv2024

CD4+ T cells drive corneal nerve damage but are dispensable for corneal epitheliopathy development in dry eye disease

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the cornea epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naive CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelia damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/586336v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1138e85org.highwire.dtl.DTLVardef@f1d0c7org.highwire.dtl.DTLVardef@1c1cccaorg.highwire.dtl.DTLVardef@6c09a7_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementDry eye is a frequent ocular disorder in which damage to the corneal epithelium and nerves is triggered by inadequate lubrication. The local CD4+ T cell-predominant immune response aggravates ocular surface impairment but the exact contribution of these cells to corneal epithelial and neural disease remains undetermined. Using adoptive transfer of T cells into T cell-deficient mice, trigeminal transcriptomics, and tear cytokine analysis, we delineate the pathogenic role of CD4+ T cells, revealing that they drive corneal nerve damage but are dispensable for epithelial disease to develop in response to desiccation. CD4+ T cells promote corneal neuropathy possibly by releasing proinflammatory cytokines onto the ocular surface. These findings have implications for T cell-targeting therapies currently used for dry eye.

immunology↗