title: A TCR affinity threshold regulates memory CD4 T cell differentiation following vaccination.
abstract: Diverse Ag-specific memory TCR repertoires are essential for protection against pathogens. Subunit vaccines that combine peptide or protein Ags with TLR agonists are very potent at inducing T cell immune responses, but their capacity to elicit stable and diverse memory CD4 T cell repertoires has not been evaluated. In this study, we examined the evolution of a complex Ag-specific population during the transition from primary effectors to memory T cells after peptide or protein vaccination. Both vaccination regimens induced equally diverse effector CD4 TCR repertoires, but peptide vaccines skewed the memory CD4 TCR repertoire toward high-affinity clonotypes whereas protein vaccines maintained low-affinity clonotypes in the memory compartment. CD27-mediated signaling was essential for the maintenance of low-affinity clonotypes after protein vaccination but was not sufficient to promote their survival following peptide vaccination. The rapid culling of the TCR repertoire in peptide-immunized mice coincided with a prolonged proliferation phase during which low-affinity clonotypes disappeared despite exhibiting no sign of enhanced apoptosis. Our study reveals a novel affinity threshold for memory CD4 T cell differentiation following vaccination and suggests a role for nonapoptotic cell death in the regulation of CD4 T cell clonal selection.
authors: BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, WI 53226, USA.
authors: Christina K
authors: CK
authors: Baumgartner
authors: Hideo
authors: H
authors: Yagita
authors: Laurent P
authors: LP
authors: Malherbe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002999:Clone Cells; D003574:Cytochrome c Group / Q000008:administration & dosage / Q000276:immunology*; D007156:Immunologic Memory; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009036:Moths; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism* / Q000502:physiology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D003574:Cytochrome c Group; D011948:Receptors, Antigen, T-Cell; D022223:Vaccines, Subunit