Activation of Human Mature T Lymphocytes Through TCR Engagement in the Presence of IL-7 Can Induce Receptor Revision
Posted on: Thursday, 17 June 2004, 06:00 CDT
We previously demonstrated that receptor revision occurs in vivo in a variant T cell subpopulation with defective expression of the TCR/CD3 complex. Interestingly, these variant T cells were found at a 10-fold increased frequency in the peripheral blood of patients with chromosome instability syndromes. The physiological roles of receptor revision, i.e., rescue of T cells with defective antigen receptor expression and diversification of the peripheral T cell repertoire, appear to be particularly important for these patients, that we demonstrated to completely lack the peripheral naive T cell compartment. However, the reactivation of V(D)J recombination in mature T lymphocytes also carries appreciable risks, including those of chromosomal translocations secondary to RAG-induced DNA doublestrand breaks (DSB) and indeed, patients with chromosome instability syndromes are particularly susceptible to the development of leukemia and lymphoma. Accumulating evidence in our lab suggests that the in vitro activation of human mature T lymphocytes with 1) anti-CD3 plus anti-CD28, 2) the cognate antigen presented by dendritic cells or 3) a superantigen, induces in the presence of the lymphoid differentiation cytokine IL-7 RAG genes expression and secondary V(D)J rearrangements. When successful, these rearrangements can change the antigen specificity of activated cells, as demonstrated by tetramer staining and functional analysis. We are presently tiying to trace the molecular pathways that are initiate by these stimuli and lead to the T cell decision to rearrange once more. The in vitro model of secondary rearrangement we are presently developing will help explain in more detail both the physiological role and the pathological risk connected with T cell receptor revision in humans.
This work has been partially supported by ONLUS Fondazione Bertolini, Turin.
E. Lantelme1, S. Mantovani2, V. Turinetto1, P. Porcedda1, M. De Marchi1, C. Giachino1,2
1 Department of Clinical and Biological Sciences, University of Turin, Orbassano (Turin), Italy; 2 IRCCS Maugeri Foundation, Pavia, Italy
Copyright Edizioni Minerva Medica Mar 2004
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