Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Immunologic Research
Published in: Immunologic Research 2-3/2009

01-12-2009

Unravelling the mechanisms of help for CD8+ T cell responses

Authors: Alexandra M. Livingstone, Elizabeth B. Wilson, Fernando Ontiveros, Jyh-Chiang E. Wang

Published in: Immunologic Research | Issue 2-3/2009

Login to get access

Abstract

CD8+ T cells are critically important for immune defense against many viral and bacterial pathogens, and are also key components of cancer immunotherapy. Help from CD4+ T cells is usually essential for optimal CD8+ T cell responses, driving the primary response, the survival of memory cells, and the generation of protective and therapeutic immunity. Understanding the mechanisms of help is thus essential for vaccine design, and for restoring protective immunity in immunosuppressed individuals. Our laboratory has developed an immunization protocol using peptide-pulsed dendritic cells to stimulate help-dependent primary, memory, and secondary CD8+ T cell responses. We have used gene-targeted and T cell receptor transgenic mice to identify two distinct pathways that generate help-dependent and help-independent CD8+ T cell responses, respectively, and are now starting to define the molecular mechanisms underlying these two pathways.
Literature
1.
2.
Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science. 2003;300:337–9.CrossRefPubMed
3.
Sun JC, Bevan MJ. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science. 2003;300:339–42.CrossRefPubMed
4.
Castellino F, Germain RN. Chemokine-guided CD4+ T cell help enhances generation of IL-6RalphahighIL-7Ralpha high prememory CD8+ T cells. J Immunol. 2007;178:778–87.PubMed
5.
Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature. 2006;440:890–5.CrossRefPubMed
6.
Le Bon A, Etchart N, Rossmann C, Ashton M, Hou S, Gewert D, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol. 2003;4:1009–15.CrossRefPubMed
7.
Sun JC, Bevan MJ. Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J Immunol. 2004;172:3385–9.PubMed
8.
Wang JC, Livingstone AM. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo. J Immunol. 2003;171:6339–43.PubMed
9.
Bourgeois C, Rocha B, Tanchot C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science. 2002;297:2060–3.CrossRefPubMed
10.
Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 2003;421:852–6.CrossRefPubMed
11.
Sun JC, Williams MA, Bevan MJ. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol. 2004;5:927–33.CrossRefPubMed
12.
Fernando GJ, Khammanivong V, Leggatt GR, Liu WJ, Frazer IH. The number of long-lasting functional memory CD8+ T cells generated depends on the nature of the initial nonspecific stimulation. Eur J Immunol. 2002;32:1541–9.CrossRefPubMed
13.
Livingstone AM, Kuhn M. Dendritic cells need T cell help to prime cytotoxic T cell responses to strong antigens. Eur J Immunol. 1999;29:2826–34.CrossRefPubMed
14.
Livingstone AM, Kuhn M. Peptide-pulsed splenic dendritic cells prime long-lasting CD8(+) T cell memory in the absence of cross-priming by host APC. Eur J Immunol. 2002;32:281–90.CrossRefPubMed
15.
Badovinac VP, Messingham KA, Jabbari A, Haring JS, Harty JT. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nat Med. 2005;11:748–56.CrossRefPubMed
16.
Harty JT, Badovinac VP. Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol. 2008;8:107–19.CrossRefPubMed
17.
Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–96.CrossRefPubMed
18.
19.
Ontiveros F. The influence of innate immune mechanisms on CD4+ and CD8+ T cell responses. University of Rochester, Rochester, USA; 2008.
20.
Wilson EB, Livingstone AM. Cutting Edge: CD4+ T cell-derived IL-2 is essential for help-dependent primary CD8+ T cell responses. J Immunol. 2008;181:7445–8.PubMed
21.
Barnden MJ, Allison J, Heath WR, Carbone FR. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol. 1998;76:34–40.CrossRefPubMed
22.
Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature. 1998;393:478–80.CrossRefPubMed
23.
Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998;393:474–8.CrossRefPubMed
24.
Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393:480–3.CrossRefPubMed
25.
26.
Schuurhuis DH, Laban S, Toes RE, Ricciardi-Castagnoli P, Kleijmeer MJ, van der Voort EI, et al. Immature dendritic cells acquire CD8(+) cytotoxic T lymphocyte priming capacity upon activation by T helper cell-independent or -dependent stimuli. J Exp Med. 2000;192:145–50.CrossRefPubMed
27.
Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.PubMed
28.
Tanchot C, Rocha B. CD8 and B cell memory: same strategy, same signals. Nat Immunol. 2003;4:431–2.CrossRefPubMed
29.
Lee BO, Hartson L, Randall TD. CD40-deficient, influenza-specific CD8 memory T cells develop and function normally in a CD40-sufficient environment. J Exp Med. 2003;198:1759–64.CrossRefPubMed
30.
Wang J-C. The role of CD4+ T help for primary and memory CD8+ T cell responses against non-infectious antigens. University of Rochester, Rochester, USA; 2006.
31.
Behrens GM, Li M, Davey GM, Allison J, Flavell RA, Carbone FR, et al. Helper requirements for generation of effector CTL to islet beta cell antigens. J Immunol. 2004;172:5420–6.PubMed
32.
Hernandez J, Aung S, Marquardt K, Sherman LA. Uncoupling of proliferative potential and gain of effector function by CD8(+) T cells responding to self-antigens. J Exp Med. 2002;196:323–33.CrossRefPubMed
33.
Ahonen CL, Doxsee CL, McGurran SM, Riter TR, Wade WF, Barth RJ, et al. Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN. J Exp Med. 2004;199:775–84.CrossRefPubMed
34.
Sojka DK, Bruniquel D, Schwartz RH, Singh NJ. IL-2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J Immunol. 2004;172:6136–43.PubMed
35.
Yang L, Mosmann T. Synthesis of several chemokines but few cytokines by primed uncommitted precursor CD4 T cells suggests that these cells recruit other immune cells without exerting direct effector functions. Eur J Immunol. 2004;34:1617–26.CrossRefPubMed
36.
Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med. 2004;200:1613–22.CrossRefPubMed
37.
McDyer JF, Li Z, John S, Yu X, Wu CY, Ragheb JA. IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production. J Immunol. 2002;169:2736–46.PubMed
38.
Bachmann MF, Wolint P, Walton S, Schwarz K, Oxenius A. Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur J Immunol. 2007;37:1502–12.CrossRefPubMed
39.
Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006;441:890–3.CrossRefPubMed
40.
Banchereau J, Pascual V, Palucka AK. Autoimmunity through cytokine-induced dendritic cell activation. Immunity. 2004;20:539–50.CrossRefPubMed
41.
Curtsinger JM, Valenzuela JO, Agarwal P, Lins D, Mescher MF. Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol. 2005;174:4465–9.PubMed
42.
Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med. 2005;202:637–50.CrossRefPubMed
43.
Janssen E, Tabeta K, Barnes MJ, Rutschmann S, McBride S, Bahjat KS, et al. Efficient T cell activation via a toll-interleukin 1 receptor-independent pathway. Immunity. 2006;24:787–99.CrossRefPubMed
44.
MartIn-Fontecha A, Sebastiani S, Hopken UE, Uguccioni M, Lipp M, Lanzavecchia A, et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med. 2003;198:615–21.CrossRefPubMed
45.
Joshi NS, Kaech SM. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J Immunol. 2008;180:1309–15.PubMed
46.
Janssen EM, Droin NM, Lemmens EE, Pinkoski MJ, Bensinger SJ, Ehst BD, et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature. 2005;434:88–93.CrossRefPubMed
Metadata
Title
Unravelling the mechanisms of help for CD8+ T cell responses
Authors
Alexandra M. Livingstone
Elizabeth B. Wilson
Fernando Ontiveros
Jyh-Chiang E. Wang
Publication date
01-12-2009
Publisher
Humana Press Inc
Published in
Immunologic Research / Issue 2-3/2009
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-009-8102-0

Other articles of this Issue 2-3/2009

Immunologic Research 2-3/2009 Go to the issue

OriginalPaper

Immunology at the University of Rochester

OriginalPaper

An approach to the identification of T cell epitopes in the genomic era: application to Francisella tularensis

OriginalPaper

Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets

OriginalPaper

The platelet as an immune cell—CD40 ligand and transfusion immunomodulation

OriginalPaper

T helper cytokine patterns: defined subsets, random expression, and external modulation

OriginalPaper

Lysophosphatidic acid and autotaxin: emerging roles in innate and adaptive immunity