CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes

@article{Janssen2003CD4TC,
  title={CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes},
  author={Edith M. Janssen and Edward E. Lemmens and Tom Wolfe and Urs Christen and Matthias v. Herrath and Stephen P. Schoenberger},
  journal={Nature},
  year={2003},
  volume={421},
  pages={852-856}
}
A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (TH) 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 TH cells. A clearer understanding of the contribution of TH cells to CTL development has been hampered by the fact… 
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TLDR
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TLDR
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References

SHOWING 1-10 OF 29 REFERENCES
Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells
TLDR
It is reported that C57BL/6J and AKR/J mice, when functionally depleted of CD4+ cells by in vivo treatment with the CD4-specific rat monoclonal antibody GK1.5, responded to ectromelia virus infection and subsequently recovered from the disease that was lethal for similarly infected nude mice (CD4−, CD8−).
Help for cytotoxic-T-cell responses is mediated by CD40 signalling
TLDR
It is shown that signalling through CD40 on the antigen-presenting cells can replace the requirement for TH cells, indicating that T-cell ‘help’, at least for generation of CTLs by cross-priming, is mediated by signalling throughCD40 onThe antigen- presenting cell.
T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions
Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes,, the nature of the ‘help’ provided to CTLs is unknown. One widely
Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help
TLDR
It is shown that CTL induction by cross-priming with cell-associated ovalbumin requires the active involvement of CD4+ helper T cells, and it is argued that the cognitive nature of this event suggests that theCD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.
Long-lasting CD8 T cell memory in the absence of CD4 T cells or B cells
TLDR
The results suggest that CD8 memory is CD4 independent and that there is no requirement for long term retention of immune complexes on follicular dendritic cells, nor for B cells as antigen- presenting cells.
Role of CD28-B7 Interactions in Generation and Maintenance of CD8 T Cell Memory
TLDR
In CD28−/− mice, LCMV-specific memory CD8 T cells showed normal homeostatic proliferation in vivo and also conferred protective immunity, indicating that CD28 signaling is not necessary for the proliferative renewal and maintenance of memory CD 8 T cells.
Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4
TLDR
In these mice, the development of CD8+ T cells and myeloid components is unaltered, indicating that expression of CD4 on progenitor cells and CD4+CD8+ (double positive) thymocytes is not obligatory, which is important to the understanding of immune disorders, including AIDS.
Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division.
TLDR
In this study, in vitro and in vivo the differentiation of naive CTL into effector and memory CTL as a function of cell division using lymphocytic choriomeningitis virus-specific TCR-transgenic spleen cells labeled with the vital dye carboxyfluorescein diacetate, succinimidyl ester is investigated.
Cutting Edge: Precursor Frequency Affects the Helper Dependence of Cytotoxic T Cells1
TLDR
It is suggested that when precursor frequencies are high, priming of CD8 T cell responses may not require CD4 T cell help, and this report shows that CTL responses induced by cross-priming can be converted from CD4-dependent toCD4-independent by increasing the frequency of CTL precursors.
A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell
TLDR
It is found that the three cells need not meet simultaneously but that the helper cell can first engage and ‘condition’ the dendritic cell, which then becomes empowered to stimulate a killer cell.
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