title: Antigen-specific activation thresholds of CD8+ T cells are independent of IFN-I-mediated partial lymphocyte activation.
abstract: Type-I IFN (IFN-I) are highly pleiotropic cytokines known to modulate immune responses and play an early central role in mediating antiviral defenses. We have shown that IFN-I mediate transient up-regulation of a distinct subset of lymphocyte surface activation markers on both B and T cells in vivo independent of cognate antigen: a state referred to as 'partial lymphocyte activation'. Here we investigated in vitro the possibility that partial lymphocyte activation may serve to lower the antigen-specific activation thresholds for T cells. We found that the kinetics of Ca(2+) flux in T cells responding to TCR cross-linking was not enhanced in partially activated T cells. Furthermore, following TCR stimulation with anti-cluster of differentiation (CD) 3 epsilon, a lower proportion of partially activated than naive T cells proliferated. In contrast, the proliferation of partially activated and naive ovalbumin peptide (OVAp, SIINFEKL) specific CD8(+) T cells (OT-I CD8(+) T cells) was similar when stimulated with OVAp. Surprisingly, using an enzyme-linked immunospot (ELISPOT) assay for IFN-gamma secretion, we found that a higher number of partially activated OT-I CD8(+) T cells expressed effector functions than did naive OT-I CD8(+) T cells. This is most readily explained by an increased survival of activated antigen-specific CD8(+) T cells from a pool of partially activated T cells than naive T cells. Overall, when examining the effects of early (Ca(2+) flux), intermediate (proliferation) or late events (IFN-gamma secretion) of T-cell activation, we found that partial activation promotes the survival but does not alter the antigen-specific activation thresholds of CD8(+) T cells.
authors.affiliation: Viral Immunology, Emerging Pathogens and Vaccines Program, John Curtin School of Medical Research, Acton, ACT 0200, Canberra, Australia. danushka.wijesundara@anu.edu.au
authors.forename: Danushka K
authors.initials: DK
authors.lastname: Wijesundara
authors.forename: Sheetal
authors.initials: S
authors.lastname: Kumar
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alsharifi
authors.forename: Arno
authors.initials: A
authors.lastname: Müllbacher
authors.forename: Matthias
authors.initials: M
authors.lastname: Regner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000941:Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D017252:CD3 Complex; C485468:Cd3e protein, mouse; D007370:Interferon Type I; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D010047:Ovalbumin