Abstract
TNF, lymphotoxin (LT) and their receptors are expressed constitutively in the thymus. It remains unclear whether these cytokines play a role in normal thymic structure or function. We have investigated thymocyte differentiation, selection and thymic organogenesis in gene targeted mice lacking LTα, TNF, or both (TNF/LTα-/-). The thymus was normal in TNF/LTα-/- mice with regard to cell yields and stromal architecture. Detailed analysis of αβ and γδ T cell-lineage thymocyte subsets revealed no abnormalities, implying that neither TNF nor LT play an essential role in T cell differentiation or positive selection. The number and distribution of thymic CD11c+ dendritic cells was also normal in the absence of both TNF and LTα. A three-fold increase in B cell numbers was observed consistently in the TNF/LTα-/- thymus. This phenotype was due entirely to the LTα deficiency and associated with changes in the hemopoietic compartment, rather than the thymic stromal compartment of LTα-/- mice. Finally, specific Vβ8+ T cell deletion within the thymus following intrathymic injection of staphylococcal enterotoxin B (SEB) was TNF/LT independent. Thus, despite the presence of these cytokines and their receptors in the normal thymus, there appears no essential role for either TNF or LT in development of organ structure or for those processes associated with T cell repertoire selection.
Highlights
The thymus provides the microenvironment necessary for the development of T cells from lymphoid progenitor cells as well as for selective elimination of T cells that are potentially autoreactive
To determine whether the absence of both TNF and LT affected the integrity of the thymus, TNF/LTct-/thymuses were examined for gross structural abnormalities and for microarchitectural changes
Several studies have suggested a role for TNF and LT in thymocyte proliferation and differentiation, and in negative selection (Suda et al, 1990; Suda et al, 1990; Suda and Zlotnik, 1992; Suda and Zlotnik, 1992; Zuniga-Pflucker et al, 1995)
Summary
The thymus provides the microenvironment necessary for the development of T cells from lymphoid progenitor cells as well as for selective elimination of T cells that are potentially autoreactive. This process, termed negative selection, inhibits maturation of those cells expressing receptors reactive to self antigens and promotes the maintenance of self tolerance (Kisielow and von Boehmer, 1995). E-mail: jon.sedgwick @ dnax.org (programmed cell death) in negatively selected cells (Surh and Sprent, 1994). This appears to involve a signal through the TCR of the developing thymocyte in conjunction with second signal(s) which are as yet poorly defined (Page et al, 1993; Page et al, 1996)
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