Selective involution of thymic medulla by cyclosporine A with a decrease of mature thymic epithelia, XCR1+ dendritic cells, and epithelium-free areas containing Foxp3+ thymic regulatory T cells

• Published in: Histochemistry and cell biology Vol. 156; no. 2; pp. 133 - 146
• Main Authors: Sawanobori, Yasushi, Kitazawa, Yusuke, Ueta, Hisashi, Matsuno, Kenjiro, Tokuda, Nobuko
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2021; Springer Nature B.V
• Subjects: Animals; Autografts; Biochemistry; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Cell Biology; Cyclosporine - administration & dosage; Cyclosporine - pharmacology; Cyclosporins; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - pathology; Developmental Biology; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - pathology; Epithelium; Forkhead Transcription Factors - analysis; Forkhead Transcription Factors - metabolism; Foxp3 protein; Graft-versus-host reaction; Immunohistochemistry; Immunoregulation; Immunosuppressive agents; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacology; Injections, Subcutaneous; Lymphocytes T; Major histocompatibility complex; Male; Medulla oblongata; Microenvironments; Optical Imaging; Original Paper; Phenotypes; Rats; Rats, Inbred Lew; Receptors, Chemokine - analysis; Receptors, Chemokine - deficiency; Receptors, Chemokine - metabolism; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - pathology; Thymocytes; Thymocytes - drug effects; Thymocytes - pathology; Thymus; Thymus gland; Thymus Gland - drug effects; Thymus Gland - pathology; Thymic structure; Immunosuppressive drug; Dendritic cells; Regulatory T cells; Thymic epithelial cells; Thymus
• ISSN: 0948-6143; 1432-119X
• DOI: 10.1007/s00418-021-01993-y

Immunosuppressive drugs such as cyclosporine A (CSA) can disrupt thymic structure and functions, ultimately inducing syngeneic/autologous graft-versus-host disease together with involuted medullas. To elucidate the effects of CSA on the thymus more precisely, we analyzed the effects of CSA on the thymus and T cell system using rats. In addition to confirming the phenomena already reported, we newly found that the proportion of recent thymic emigrants also greatly decreased, suggesting impaired supply. Immunohistologically, the medullary thymic epithelial cells (mTECs) presented with a relative decrease in the subset with a competent phenotype and downregulation of class II major histocompatibility complex molecules. In control rats, thymic dendritic cells (DCs) comprised two subsets, XCR1 + SIRP1α − CD4 − and XCR1 − SIRP1α + CD4 + . The former had a tendency to selectively localize in the previously-reported epithelium-containing areas of the rat medullas, and the number was significantly reduced by CSA treatment. The epithelium-free areas, another unique domains in the rat medullas, contained significantly more Foxp3 + thymic Tregs. With CSA treatment, the epithelium-free areas presented strong involution, and the number and distribution of Tregs in the medulla were greatly reduced. These results suggest that CSA inhibits the production of single-positive thymocytes, including Tregs, and disturbs the microenvironment of the thymic medulla, with a decrease of the competent mTECs and disorganization of epithelium-free areas and DC subsets, leading to a generation of autoreactive T cells with selective medullary involution.