From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help

Abstract

CD8 + T cells play an important role in controlling pathogenic infections and are therefore key players in the immune response. It has been shown that among other factors CD4 + T cells can shape the magnitude as well as the quality of primary and/or secondary CD8 + T-cell responses. However, due to the complexity and the differences among diverse immunization or infection models, the overall requirement, the time points, as well as the specific mechanism(s) of CD4 + T-cell help may differ substantially. Here, we summarize current knowledge about the differential requirement of CD4 + T-cell help in promoting primary CD8 + T-cell responses as well as establishing functional memory CD8 + T cells in various experimental settings. Keywords: CD8 + T cells r Differentiation r Memory r T-cell help CD8 + T-cell responsesA number of different parameters influence, by virtue of their strength and composition, CD8 + T-cell activation; they subsequently also shape the size and the phenotypical and functional properties of the resultant memory CD8 + T-cell pool. These parameters include antigen-specific T-cell precursor frequencies [1], the strength of the T-cell receptor interaction with peptide-MHC complexes, and the signals provided by co-stimulatory receptors, as well as innate immune system derived inflammatory cytokines [2,3]. Among the factors that modulate the activation of dendritic cells (DCs), the cells that are the main inducers of CD8 + T-cell responses, is the help provided by CD4 + T cells. CD4 + T-cell engagement of DCs promotes the upregulation of certain costimulatory molecules (such as CD80 and CD86) on, as well as the release of pro-inflammatory cytokines such as IL-12 by, DCs. Thus, in many defined experimental settings, T helper cells have been implicated in the expansion and survival of CD8 + T cells during the primary response, and have a key role in establishing long-lived, functionally robust memory CD8 + T-cell responses [4][5][6][7]. The concept of T-cell help for CD8 + T-cell responses was Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch further supported by the finding that chemokines secreted by activated CD4 + T helper cells can play a key role in the recruitment of naïve antigen-specific CD8 + T cells to antigen-bearing antigen presenting cells (APCs) in secondary lymphoid organs [8] or to sites of infection [9]. Moreover, in some experimental settings CD4 + T cells were proposed to directly interact with CD8 + T cells, thereby promoting their activation and expansion [10]. Hence, the overall contribution, as well as the mechanism, of helper CD4 + T cells in the initiation of primary and secondary CD8 + T-cell responses is more complex than initially believed and appears to strongly depend on the specific biology of the immunization/infection system.

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

“…Our antibody depletion experiments suggest that protective immunity elicited by the 4-1BB-raptor conjugate-generated memory response was mediated in part by CD8 + T cells (Supplemental Figure 3, P = 0.0052), whereas the contribution of CD4 + T cells was not clear, though probable (Supplemental Figure 3, P = 0.064). Given the documented role of CD4 + T cell help in the recall response of memory CD8 + T cells (10,13,50), future studies will be required to examine in depth the contribution of both adaptive and innate arms of the immune response in the 4-1BB-raptor conjugate-mediated enhancement of antitumor immunity.…”

“…On day 25, the cells were harvested, washed, and plated onto 96-well round-bottom plates, with 10 replicates per condition. Five wells for each condition were treated with 0.01 nM SIINFEKL peptide overnight, and five other wells were treated with control SDYEGRLI influenza NP (50)(51)(52)(53)(54)(55)(56)(57) peptide. Eighteen hours later, 1 μCi H 3 -thymidine was added to each well.…”

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

“…In some circumstances, CD4 T cell help promotes CD8 T cell priming, as well as the secondary expansion of CD8 memory T cells (28). The ability of CD4 T cells to instill a competency for secondary CD8 T cell expansion is thought to occur during priming.…”

CD4+T Cell Help Is Dispensable for Protective CD8+T Cell Memory against Mousepox Virus following Vaccinia Virus Immunization

“…ϩ T cell help (T H ) in the form of cytokines and/or costimulation (12). It has also been shown in several infectious models that T H is required for the conditioning and/or maintenance of the CD8 M pool and/or their secondary expansion and differentiation into CD8 E (13)(14)(15)(16).…”