CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes
Abstract
A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.
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The death of helpless CTLs is mediated by TRAIL, which triggers apoptosis in helpless CTL and other activated T cells.
“The latter cell death is mediated by expression of the death ligand TRAIL, which triggers apoptosis in the helpless CTL as well as other activated T cells70,72.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [72]
TRAIL-deficient mice are resistant to tolerance induction by intravenously injected apoptotic cells.
“In support of this, TRAIL-deficient mice were resistant to tolerance induction by intravenously injected apoptotic cells72.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [72]
CD8+ T cells produce TRAIL upon re-exposure to antigen, which inhibits immunization for cell-mediated responses and mediates tolerance.
“As a result, the CD8+ T cells produce TRAIL upon re-exposure to antigen, which acts to inhibit immunization for cell-mediated responses (that is, mediate tolerance).”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [72]
DC that engulf necrotic cells present antigen to both CD4+ and CD8+ T cells, whereas those that engulf apoptotic cells present antigen to CD8+ T cells but not CD4+ T cells.
“DC that have engulfed necrotic cells present antigen to both CD4+ and CD8+ T cells, however those that engulf apoptotic cells present antigen to CD8+ T cells but not CD4+ T cells72.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [72]
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Self-citation
- Authors
- Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G., & Schoenberger, S. P.
- Affiliations
- La Jolla Institute for Immunology (US)
- Corresponding author
- Schoenberger, Stephen P.
- Venue
- Nature
- Published
- 2003-02
- Volume
- 421
- Issue
- 6925
- Pages
- 852-856
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1493822493
- Cited by
- 1,635
- References
- 28
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 37 · 2023: 46 · 2022: 37 · 2021: 42 · 2020: 58 · 2019: 42 · 2018: 52 · 2017: 36 · 2016: 41 · 2015: 61 · 2014: 63 · 2013: 63 · 2012: 71
- FWCI
- 46.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- CD4+ T cells, CD8+ T cells, cytotoxic T lymphocytes, T helper cells, secondary immune response, T cell memory, T cell help, cross-priming, antigen-presenting cells, T cell differentiation
- MeSH terms
- Animals, Antigens, Cell Line, Cytotoxicity, Immunologic, Flow Cytometry, T-Lymphocytes, Helper-Inducer, Immunologic Memory, Lymphocyte Activation, Lymphocytic choriomeningitis virus, T-Lymphocytes, Cytotoxic, Mice
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