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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-02-0401.
Submitted February 7, 2002
Accepted May 3, 2002
Creating space: An antigen-independent, CpG-induced peripheral expansion of naive and memory T lymphocytes in a full T cell compartment
Eduardo Davila, Maria G Velez, Carrie J Heppelmann, and Esteban Celis*
Immunology, Mayo Clinic, Rochester, MN, USA
* Corresponding author; email: celis{at}mayo.edu.
Many of the mechanisms that govern T-cell homeostasis remain obscure. Here we report that repeated administration of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG-ODN) into mice induces a systemic antigen-independent expansion of naive and memory T cells in a full T cell compartment. Expansion of T cells was observed on both CD4+ and CD8+ T-cell subsets and was produced not by inducing the proliferation of the cells but by preventing their death. The anti-apoptotic effects of CpG-ODN on T cells were observed against activation-induced death and growth factor withdrawal mediated death. The ability of CpG-ODN to protect T cells from these forms of death was associated with the up-regulation of anti-apoptotic gene products including c-FLIP, bcl-xL and to some extent bcl-2. The effect of CpG-ODN on naive and memory T cells required the expression of CD28 and was not dependent on the presence of mature B lymphocytes, suggesting that other APC that respond to CpG-ODN such as dendritic cells may provide anti-apoptotic signals to T cells in an antigen-independent but CD28/B7-dependent fashion. The present findings suggest that CpG-ODN can disrupt normal T cell homeostasis not by acting as a mitogen but by preventing T cell death that normally takes place as mechanism to maintain steady state levels of T cells. These findings support a potential mean to expeditiously replenish and maintain the peripheral lymphocyte population after severe immunodepletion such as occurs in HIV-infected individuals and individuals undergoing cytoablative therapies.
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