Direct type I interferon (IFN) signaling on T cells is necessary for the proper expansion, differentiation, and survival of responding T cells following infection with viruses prominently inducing type I IFN. The reasons for the abortive response of T cells lacking the type I IFN receptor (Ifnar1(-/-)) remain unclear. We report here that Ifnar1(-/-) T cells were highly susceptible to natural killer (NK) cell-mediated killing in a perforin-dependent manner. Depletion of NK cells prior to lymphocytic choriomeningitis virus (LCMV) infection completely restored the early expansion of Ifnar1(-/-) T cells. Ifnar1(-/-) T cells had elevated expression of natural cytotoxicity triggering receptor 1 (NCR1) ligands upon infection, rendering them targets for NCR1 mediated NK cell attack. Thus, direct sensing of type I IFNs by T cells protects them from NK cell killing by regulating the expression of NCR1 ligands, thereby revealing a mechanism by which T cells can evade the potent cytotoxic activity of NK cells.

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.

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Two subsets of CD81 T cells are generated early during an immune response; one of these subsets forms the memory pool, known as memory precursor effector cells (MPECs), identified by high expression of CD127 and low expression of KLRG1, whereas the other subset forms short-lived effector cells (SLECs) identified by low expression of CD127 and high expression of KLRG1. Here, we studied in vivo the role of type-I IFN in this fate decision. We found that under priming conditions dominated by type-I IFN, as observed in lymphocytic choriomeningitis virus (LCMV) infection, type-I IFN signaling directly impacted the regulation of T-bet and thus the early fate decision of CD8 1 T cells. In the absence of type-I IFN signaling, CD8 1 T cells failed to form SLECs but could form MPECs that give rise to functional memory CD8 1 T cells. Together, these findings identify type-I IFN as an important factor driving SLEC differentiation and thus instructing the early division between the effector and memory precursor CD8 1 T-cell pool.Key words: CD8 1 T cells . Differentiation . Type I interferon . Viral infection Supporting Information available online IntroductionIn response to an acute infection CD8 1 T cells rapidly expand to form a pool of effector cells with cytolytic and cytokine secretion activity. The pool of early effector cells can be divided into two main subsets according to their ability to form terminally differentiated effector cells or long-lived memory cells; referred to as short-lived effector cells (SLECs), CD127 low and KLRG1 high , and as memory precursor effector cells (MPECs), CD127 high and KLRG1 low , respectively [1,2]. There is strong evidence that inflammatory cytokines present during CD8 1 T-cell priming play a key role in the effector and memory fate decision process [3][4][5]. In support of this notion it has been shown that IL-12 signaling is mandatory for driving activated CD8 1 T cells toward an SLEC phenotype upon infection with Listeria monocytogenes but not vesicular stomatitis virus (VSV), vaccinia virus (VV) or lymphocytic choriomeningitis virus (LCMV) [5]. Similar to IL-12, type-I IFN signaling has been shown to support the proliferation and development of cytolytic activity of CD8 1 T cells in vitro [6][7][8][9][10] and can act as an adjuvant in vivo to a variety of stimuli [3,[11][12][13][14]. (Fig. 3B). As the differences in the expression of CD25 and CD62L were already apparent during the initial cell divisions, we reasoned that very early following infection activated CD8 1 T cells undergo a lineage choice and that type-I IFN plays a crucial role in this decision.Having analyzed the very early stages of this differentiation process we next looked at the long-term development of memory cells by phenotypically analyzing cell surface marker expression profiles on WT and IFNAR À/À P14 cells in the blood of LCMV8.7and VVG2 co-infected mice (Fig. 3C). This longitudinal analysis revealed that IFNAR À/À P14 cells initially begin to down-regulate surface CD62L expression but after day 3 the ...

Certain virus infections depend on the presence of T cell help for the generation of primary CD8+ T cell responses. However, the mechanisms that render these particular viral infections T cell help dependent is largely unknown. In this study, we compared CD8+ T cell responses elicited by lymphocytic choriomeningitis virus infection, as prototype of a T cell help independent infection, with T cell help dependent CD8+ T cell responses induced by vaccinia virus infection. In this paper, we show that a key parameter decisive for T cell help independence is the ability of an infectious agent to stimulate early and robust production of type I IFN. Experimental provision of type I IFN during VV infection rendered the ensuing CD8+ T cell response completely T cell help independent. Our results support a model in which type I IFN has to be present during the first 3 d of Ag encounter and has to act directly on the responding CD8+ T cells to promote their survival and effector differentiation. We show that type I IFN signaling on responding CD8+ T cells induces profound upregulation of CD25 and increased IL-2 expression; however, neither this nor IL-15 accounts for the type I IFN effects on responding CD8+ T cells. Thus, type I IFN can effectively replace the requirement of T cell help by directly promoting CD8+ T cell survival and differentiation independent of the type I IFN-induced cytokines IL-2 and IL-15.

Wiesel M, Walton S, Richter K, Oxenius A. Virus-specific CD8 T cells: activation, differentiation and memory formation. APMIS 2009; 117: 356-81. CD8 T cells are pivotal for the control of many intracellular pathogens, and besides their role in immediate control of infections, CD8 T cells have the capacity to differentiate into long-lived antigenindependent memory CD8 T cells, at least in situations of acute and resolved infections. The population of memory cells is heterogeneous with respect to their phenotype, their anatomical localization and their functional capacities in order to afford optimal protection against secondary infections. In the past years, it has become clear that multiple in vivo parameters are involved in shaping the composition of the memory CD8 T cell population, including antigen load, duration and strength of CD8 T cell stimulation, the level of inflammation, availability of CD4 T cell help and CD8 T cell precursor frequencies. With respect to the timing when CD8 T cells are committed to become memory cells, several models have been proposed. In contrast to acute, resolved infection, the continued in vivo exposure to high levels of antigen during persistent chronic viral infection precludes the development of long-lived antigen-independent memory CD8 T cells and might even result in severe dysfunction of virus-specific CD8 T cells.

The requirements for the generation of fully competent long-lived memory CD8 T cells and in particular the role and the mechanisms of help from CD4 T cells remain ill-defined. Memory CD8 T cells generated in the absence of CD4 T cell help often have an impaired recall proliferation and are thus unable to confer protection against certain pathogens. However, the timing and the mechanisms involved in the delivery of help are still unclear and differ between various experimental systems. In this study, we investigated the role of CD4 T help in generating memory CD8 T cells in a defined heterologous prime-boost system, consisting of priming with replication incompetent virus-like particles and challenge with recombinant vaccinia virus, both sharing only a common lymphocytic choriomeningitis virus-derived CD8 T cell epitope. We show in this system that delivery of help is only essential during the challenge phase for recall proliferation of memory CD8 T cells. Furthermore, we show that generation of proliferation-competent memory CD8 T cells is independent of CD40 and CCR5 and that in vivo IL-2 supplementation neither during priming nor during challenge was able to rescue recall proliferation of “unhelped” memory CD8 T cells.