Characterization of lymphoid compartments and hematopoiesis in a TSLP transgenic mouse model

Immunodeficiencies are severe diseases, which are inherited or acquired after cytotoxic treatment or radiotherapy. Hematopoietic stem cell transplantation (HSCT) has become a common treatment for patients suffering from immunodeficiency, but especially the re-establishment of a functional T cell pool is often delayed and patients suffer from infections and relapse of malignancies. The generation of an adequate T cell pool can be achieved by de novo generation and peripheral expansion of donor T cells. However, T cell development after pretransplantational treatment is often impaired due to damage of the thymic environment. To improve thymic engraftment and preserve the thymic microenvironment, current treatments involve application of cytokines, which have often severe side effects. Therefore it is important to find alternative ways to improve T cell reconstitution after HSCT.
LTi cells are members of the family of innate lymphoid cells group 3 (ILC3s), which promote lymphoid tissue generation and are involved in tissue remodelling in primary and secondary lymphoid organs. In my study, I wanted to investigate the impact of ILC3s and secondary lymphoid organs on T cell reconstitution after HSCT. Therefore immunodeficient Rag2-/-γc-/- mice, which have reduced numbers of ILC3s and severe defects in LN development and K14 TSLP+/- Rag2-/- γc-/- mice with increased numbers of ILC3s were compared before and after transplantation with hematopoietic stem cells or mature T cells.
Characterization of the recipient mice showed that TSLP overexpression in Rag2-/-γc-/- mice increases the number of double negative thymocytes DN2 and DN3s, and improves the thymic architecture with the development of mTECs and Aire expression. Reconstitution of the hematopoietic system with fetal liver (FL) HSCs from TSLPR-/- mice showed that TSLP overexpression results in an accelerated T cell reconstitution in the thymus and peripheral organs. The reconstitution of B cells did not differ between Rag2-/-γc-/- and K14 TSLP+/- Rag2-/-γc-/- mice, suggesting that the reconstitution itself was equally efficient.
T cells depend on IL-7, as this cytokine promotes T cell proliferation and survival. I could show that the IL-7 expression was significantly higher in the spleen of K14 TSLP+/- Rag2-/-γc-/- compared to Rag2-/-γc-/- mice most likely as a result of higher numbers of dendritic cells (DCs) expressing IL-7. Finally, I could demonstrate that TSLP overexpression increases T cell proliferation in secondary lymphoid organs.
Taken together, these data suggest, that TSLP overexpression accelerates T cell reconstitution by improving de novo T cell development in the thymus and T cell expansion in secondary lymphoid organs.