Inflammatory cytokines as a third signal for T cell activation

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CD8 T cells require a third signal, along with Ag and costimulation, to make a productive response and avoid death and/or tolerance induction. Recent studies indicate that IL-12 and Type I IFN (IFNα/β) are the major sources of signal 3 in a variety of responses, and that the two cytokines stimulate a common regulatory program involving altered expression of about 350 genes. Signal 3-driven chromatin remodeling is likely to play a major role in this regulation. Although less well studied, there is emerging evidence that CD4 T cells may also require a ‘third signal’ for a productive response and that IL-1 can provide this signal. Signal 3 cytokines can replace adjuvants in supporting in vivo T cell responses to peptide and protein antigens, and a better understanding of their activities and mechanisms should contribute to more rational design of vaccines.

Introduction

T cells proliferate and differentiate in response to signals from the TCR and costimulatory receptors, predominantly CD28, and the differentiation pathway can be influenced by additional signals from the environment to result in diverse phenotypic and functional outcomes. The cytokine milieu experienced by Ag-activated CD4 T cells determines the spectrum of cytokines that will be produced by the resulting effector cells. Much is known about the identities and regulation of transcription factors that control this skewing to yield TH1, TH2, or TH17 CD4 T cells, and chromatin remodeling plays a central role in these differentiation processes. Although not as extensively studied, the differentiation fate of Ag-activated CD8 T cells is influenced in a similar manner and involves regulation of many of the same transcription factors.

For CD8 T cells, signals provided by inflammatory cytokines also have a more fundamental role in regulating responses. TCR and costimulatory signals initiate proliferation of naïve cells, but in the absence of a specific cytokine signal the cells fail to develop optimal effector functions, survive poorly, and do not form a responsive memory population [1]. Thus, inflammatory cytokines act as a ‘switch’ that determines whether Ag and costimulatory signals lead to tolerance in their absence (deletion/anergy), or in their presence, a productive response leading to strong effector functions, survival, and memory formation (Figure 1). Because this cytokine signal is required for a productive response, along with TCR (signal 1) and costimulatory signals (signal 2, including IL-2), it has been termed ‘signal 3’. The requirement for a signal 3 inflammatory cytokine provides a means for a CD8 T cell that encounters Ag to determine if there is ‘danger’ present, and to respond accordingly. In vitro experiments initially identified IL-12 and IFNα/β as having signal 3 activity for CD8 T cells, and more recent evidence indicates that they may be the predominant sources of signal 3 for CD8 T cell responses to a variety of in vivo stimuli. The molecular mechanisms involved in the effects of IL-12 and IFNα/β are beginning to be elucidated, and appear to include cytokine-driven chromatin remodeling. Although less well studied, recent evidence suggests that like CD8 T cells, naïve CD4 T cells may also require a cytokine-dependent ‘signal 3’ for a productive response to Ag, and that this may be provided by IL-1.

Section snippets

Signal 3 cytokine requirements for CD8 T cell responses

In vitro studies using artificial APC (aAPC) provided the initial evidence that IL-12 and IFNα/β could provide a crucial third signal, along with Ag and B7-1, to enhance CD8 T cell clonal expansion, and promote development of effector functions including cytolytic activity and IFNγ production [2, 3]. In vivo studies examining peptide immunization models demonstrated that these cytokines could replace the need for adjuvant by acting directly on the CD8 T cells to convert tolerance induction to a

Molecular basis of signal 3-dependent differentiation

There are numerous reports of IL-12 influencing the expression of a variety of proteins in CD8 T cells. As an initial approach to understanding the molecular basis of signal 3 cytokine effects on naïve cells, global cytokine-dependent regulation of gene expression was determined over the course of a 3-day in vitro response by naïve CD8 T cells [28••]. Stimulation of naïve cells for 72 h with aAPC having Ag and B7-1 on the surface (two signals), resulted in altered expression of about 2300 genes.

Do naïve CD4 T cells require a third signal?

Earlier work had suggested that IL-1 might provide a third signal to support CD4 T cell responses. CD4 T cells respond minimally to immunization with peptide Ag in the absence of adjuvant, but co-administration of IL-1 substantially enhanced proliferation and differentiation in response to the Ag [43]. IL-12 did not have this effect, despite its important role in skewing CD4 T cell responses. Thus, IL-12 could replace the need for adjuvant in supporting a CD8 T cell response to peptide Ag [5]

Conclusions

There is now considerable evidence that CD8 T cells need a third signal, along with Ag and costimulation, to undergo robust clonal expansion, develop strong effector functions, and form a responsive memory population. Recent studies are indicating that IL-12 and Type I IFN are the predominant sources of this third signal for a variety of responses to transplanted tissue, tumors, pathogens, and adjuvant-based vaccines. Either cytokine can support responses, and which plays the dominant role for

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The work summarized here from our laboratory was supported by National Institutes of Health Grants RO1 AI34824 and PO1AI35296.

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