TGF-β Released by Apoptotic T Cells Contributes to an Immunosuppressive Milieu

Abstract

T cell apoptosis is critical to development and homeostasis of the immune system. The most salient feature of apoptosis is the lack of an attendant inflammatory response or tissue damage. Here, we present evidence that apoptotic T cells release TGF-beta, thereby contributing to an immunosuppressive milieu. Apoptotic T cells released not only latent but also bio-active TGF-beta. Nonetheless, TGF-beta transcription was not upregulated, suggesting release of existing rather than synthesis of new TGF-beta. Localized within the intracellular membrane-bound compartment, which includes mitochondria, TGF-beta was redistributed into the cytosol following loss of mitochondrial membrane potential. TGF-beta secreted from apoptotic T cells inhibited proinflammatory cytokine production by activated macrophages to foster immune suppression. These findings broaden the potential mechanisms whereby induction of immune tolerance or deficiency occurs through T cell deletion.

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

“…Doxazosin resulted in a 'latent' induction of TGF-b1 mRNA expression that was subsequent to a moderate increase in the active TGF-b1 levels by prostate cancer cells PC-3 (after 24 h of treatment). While a similar pattern has been exhibited by apoptotic T-cells with an enhanced release of active TGF-b1 without major changes in the mRNA expression (Chen et al, 2001), one may also consider the possibility that the observed upregulation of TGF-b mRNA in prostate cancer cells could be a consequence of doxazosin-induced apoptosis. The lack of induction of TbRII expression in prostate cancer cells by doxazosin is consistent with our earlier report indicating no changes in TbRII protein levels in prostate tissue (from BPH patients) after treatment with the quinazolines (Glassman et al, 2001).…”

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

“…For the first time to our knowledge, a link between apoptotic cells and Treg expansion is reported. This could be an additional mechanism to immunomodulatory cytokine production 19,[25][26][27][28][29] or cross-tolerization [20][21][22] to prevent deleterious responses against dying cells during normal turnover. We propose to take advantage of this physiological mechanism that maintains self-tolerance to improve HC transplantation outcomes.…”

“…27 Furthermore, some cells like T cells may release TGF-b or IL-10 in the course of their apoptotic process. 28,29 Although the release of TGF-b or IL-10 during apoptosis has been extensively reported, 19,[25][26][27][28][29] capacities of apoptotic cells to induce a CD4 þ T-cell subset endowed with regulatory properties has not been demonstrated so far.…”

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

“…One could thus postulate that increased secretion of TGF-b in the response to quinazoline-mediated apoptosis prostate tissue may be attributed to dying cells releasing active TGF-b, as has been reported in apoptotic T-cells that release TGF-b protein without an increase in mRNA level. 58 Indirect support for this concept stems from observations that doxazosin treatment of PC-3 prostate cancer cells does not yield any changes in TGF-b mRNA expression over a 24 h timecourse of apoptosis induction. 42 …”