Immunisation route-dependent expression of IL-4/IL-13 can modulate HIV-specific CD8(+) CTL avidity.
All HIV-1 'systemic vaccine trials' in humans have yielded poor outcomes. Thus, it is important to understand whether the route of delivery influences the quality of protective CTL immunity. Using heterologous poxvirus immunisation we have shown that systemically (i.m./i.m.) immunised CD8(+) T cells generated higher levels of IL-4/IL-13 compared to mucosal delivery and expression also correlated with i.m./i.m. immunised mice eliciting CTL of lower avidity. Studies using IL-4(-/-) and IL-13(-/-) KO mice have shown that the capacity to express IFN-gamma, IL-4 and/or IL-13 by K(d)Gag(197-205)-specific CTL differed between these groups and was inversely correlated with CTL avidity (IL-13(-/-)>IL-4(-/-)>BALB/c), although no significant differences in the magnitude of CTL responses were observed between IL-13(-/-) and wild type mice. When IL-13 was reconstituted in IL-13(-/-) splenocytes in vitro, their ability to bind tetramers also decreased significantly. Our data reveal that total absence of IL-13 can greatly enhance CTL avidity. In contrast, extracellular IL-4 appears to be important in maintaining long-term Th1/Th2 balance in CTL, even though expression of IL-4 by CTL markedly reduced avidity. STAT6(-/-) mice also showed memory CTL of higher avidity. Furthermore, CCL5 expression in K(d)Gag(197-205)-specific CTL was also regulated by IL-4/IL-13.
Ranasinghe
Charani
C
The Australian National University, Canberra, Australia. Charani.Ranasinghe@anu.edu.au
Ramshaw
Ian A
IA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006678:HIV / Q000276:immunology; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011212:Poxviridae / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit
D018946:Chemokine CCL5; D007371:Interferon-gamma; D018793:Interleukin-13; D007376:Interleukin-2; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; C503460:Ccl5 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse