Increased Thymic B Cells but Maintenance of ThymicStructure, T Cell Differentiation and Negative Selectionin Lymphotoxin‐α and TNF Gene‐Targeted Mice

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.

Development and maturation of Langerhans cells, spleen and bone marrow dendritic cells in TNF-α/lymphotoxin-α double-deficient mice

“…We confirm our own data [32] and those of others, that mice lacking the cytokines TNF-␣ and lymphotoxin-␣ have largely normal dendritic cells [39].…”

“…Thus, our data may rather reflect the potential of dendritic cell precursors in the spleen to develop into normally functioning, mature dendritic cells in the absence of both cytokines. Similar to our observations, Grech et al [39] reported that thymic dendritic cells were normal in numbers and distribution in TNF␣ −/− /LT␣ −/− mice.…”

The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis

“…Furthermore, the spontaneous rat model of diabetic and thyroid autoimmunity (BB rat) exhibits lowered expression of TNF [30]. The latter study also linked low TNF to defective T cell maturation; TNF-a is a critical cytokine in the normal T cell negative selection in the periphery but not the thymus [30,31]. Higher levels of circulating TNF receptors are found in association with lupus activity [32,33].…”

“…The process of apoptosis occurs through the T cell receptor, fas ligand or other death pathways [74,99]. While TNF is constitutively express in the thymus [100], it does not appear to play an essential role in negative selection of early precursor T cells [31].…”

Tumor Necrosis Factor Promotes Human T‐Cell Development in Nonobese Diabetic/Severe Combined Immunodeficient Mice

“…However, T‐cell differentiation and selection, as well as the thymus architecture, are normal in TNF knockout mice. Interestingly, there is a threefold increase in B‐cell numbers in the thymus of these mice [26].…”