Immunological adjuvants promote activated T cell survival via induction of Bcl-3

Abstract

Injection of soluble protein antigen into animals causes abortive proliferation of the responding T cells. Immunological adjuvants boost T cell responses at least in part by increasing the survival of activated T cells during and after the initial proliferative phase of their clonal expansion. To understand how adjuvants promote T cell survival, we used gene microarrays to analyze gene expression in T cells activated either with antigen alone or in the presence of two different adjuvants. Among the genes whose expression was increased by both adjuvants was the IkappaB family member Bcl-3. Retroviral infection experiments showed that expression of Bcl-3 increased survival of activated T cells in vitro and in vivo. Adjuvants may therefore improve survival of activated T cells via induction of Bcl-3.

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

“…Recent findings have correlated BCL3 expression with increased cellular proliferation and survival in lymphocytes (Ong et al, 1998;Rebollo et al, 2000;Mitchell et al, 2001). Thus, we speculated that upregulation of BCL3 could contribute to the IL-6-mediated antiapoptotic effect in MM cells.…”

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

“…Hildeman et al [19] have proposed that activation-induced reactive oxygen species transcriptionally repress both Bcl-2 and Bcl-x. Moreover, a causative role for Bcl-2 repression in T cell death is supported by observations that enforced expression of Bcl-2 in superantigen-or peptide-stimulated T cells improves their survival after activation [18,32]. Both of these anti-apoptotic factors are initially expressed at high levels within 24 h of T cell stimulation [11], presumably through exposure to survival cytokines and co-stimulatory signaling, respectively [33].…”

Mutations in the NF-κB signaling pathway: implications for human disease

“…In addition, t(14;19) translocations involving BCL-3 have been identified in some lymphomas (Nakagawa et al, 1995;Yano et al, 1995;McKeithan et al, 1997;Au et al, 2002;Soma et al, 2006) and occasionally in lymphoproliferative disorders (Michaux et al, 1996); furthermore, other genetic alterations on chromosome 19 may also lead to increased BCL-3 expression (Schlette et al, 2005). The hypothesis that increased expression of BCL-3 contributes to human B-cell malignancies is supported by several findings: (1) transgenic mice in which BCL-3 is under the control of the m heavy chain enhancer develop splenomegaly and have excess mature B cells in their bone marrow and lymph nodes (Ong et al, 1998); (2) overexpression of BCL-3 can transform mouse 3T3 cells in culture (Viatour et al, 2004); (3) overexpression of BCL-3 can enhance the survival of activated T cells (Mitchell et al, 2001) and (4) elevated levels of BCL-3 are seen in many lymphoid and non-lymphoid human tumor samples (Cogswell et al, 2000;Rassidakis et al, 2003;Canoz et al, 2004;Pallares et al, 2004;Ohno et al, 2005;Schlette et al, 2005). Oncogenically activating mutations within the coding region of BCL-3 have not been identified; however, such mutations may exist in that certain point mutations can enhance the transforming activity of BCL-3 in vitro (Viatour et al, 2004).…”