Thymocyte development is normal in CTLA-4-deficient mice

Abstract

Recent studies indicate that CTLA-4 interaction with B7 ligands transduces an inhibitory signal to T lymphocytes. Mice homozygous for a null mutation in CTLA-4 have provided the most dramatic example of the functional importance of CTLA-4 in vivo. These animals develop a fatal lymphoproliferative disorder and were reported to have an increase in CD4 ؉ and CD8؉ thymocytes and CD4 ؊ CD8؊ thymocytes, and a decrease in CD4 ؉ CD8 ؉ thymocytes. Based on these observations, it was proposed that CTLA-4 is necessary for normal thymocyte development. In this study, CTLA-4-deficient mice carrying an insertional mutation into exon 3 of the ctla-4 gene were generated. Although these mice display a lymphoproliferative disorder similar to previous reports, there was no alteration in the thymocyte profiles when the parathymic lymph nodes were excluded from the thymi. Further, thymocyte development was normal throughout ontogeny and in neonates, and there was no increase in thymocyte production. Finally, T cell antigen receptor signaling, as assessed by proximal and distal events, was not altered in thymocytes from CTLA-4 ؊/؊ animals. Collectively, these results clearly demonstrate that the abnormal T cell expansion in the CTLA-4-deficient mice is not due to altered thymocyte development and suggest that the apparent altered thymic phenotype previously described was due to the inclusion of parathymic lymph nodes and, in visibly ill animals, to the infiltration of the thymus by activated peripheral T cells. Thus it appears that CTLA-4 is primarily involved in the regulation of peripheral T cell activation.

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

“…We also investigated the TCR repertoire of thymocytes in these mice by staining with mAb specific for each Vb (Vb2-14, Vb17). Similar to the results in CTLA-4 -/-mice [7,8] there was no difference in the usage of the Vb repertoire between FL-, TR-Tg mice and normal mice (data not shown). …”

“…Whether such small numbers of Treg in Tg mice are functional and sufficient for preventing the induction of the lymphoproliferative disorder remains to be determined. It appears to be established that CTLA-4 does not affect thymocyte differentiation [7][8][9][10]. Still, this is only based on the observation that three different TCR-Tg mice (HY-Tg, LCMV-Tg, and DO11.10 TCR-Tg mice) crossed with CTLA-4 -/-mice did not reveal any gross defect in thymic positive/negative selections [7][8][9][10].…”

“…It appears to be established that CTLA-4 does not affect thymocyte differentiation [7][8][9][10]. Still, this is only based on the observation that three different TCR-Tg mice (HY-Tg, LCMV-Tg, and DO11.10 TCR-Tg mice) crossed with CTLA-4 -/-mice did not reveal any gross defect in thymic positive/negative selections [7][8][9][10]. Consistent with these observations, when we crossed FLTg or TR-Tg mice with DO11.10 TCR-Tg or HY-Tg mice and analyzed thymocyte selection, we did not find any significant alternations of overall thymocyte development (unpublished observation).…”

“…It has been suggested that this lymphoproliferative disorder in CTLA-4 -/-mice is induced by polyclonal activation of peripheral T cells and that it is not due to a defect in the elimination of autoreactive T cells in the thymus [7][8][9][10], providing evidence for the in vivo function of CTLA-4 as a negative regulator of T cell responses [5,6]. However, the conclusion that CTLA-4 does not influence thymic selection was based mainly on the analyses of thymocyte development in TCR-transgenic (Tg) Â CTLA-4-deficient mice [7][8][9][10].…”

Role of CTLA-4 in the Activation of Single- and Double-Positive Thymocytes

“…Some studies using CTLA-4-deficient mice showed that thymocyte development is not altered in the absence of CTLA-4 (26,27), suggesting that CTLA-4 is not involved in thymocyte development. Other studies showed that the administration of CTLA-4-neutralizing Abs inhibited negative selection in vivo (13), suggesting that CTLA-4 is necessary for negative selection.…”