title: Th cells promote CTL survival and memory via acquired pMHC-I and endogenous IL-2 and CD40L signaling and by modulating apoptosis-controlling pathways.
abstract: Involvement of CD4(+) helper T (Th) cells is crucial for CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity. However, CD4(+) Th's signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4(+) Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4(+) T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA)-pulsed dendritic cell (DCova). CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2K(b)/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I) complex signaling, CD4(+) Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4(+) Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7) molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4(+) Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada.
authors.forename: Channakeshava Sokke
authors.initials: CS
authors.lastname: Umeshappa
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.forename: Shulin
authors.initials: S
authors.lastname: Xu
authors.forename: Roopa Hebbandi
authors.initials: RH
authors.lastname: Nanjundappa
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.forename: Yulin
authors.initials: Y
authors.lastname: Deng
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D016000:Cluster Analysis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D023201:CD40 Ligand