Immunology

A helpers' guide to infection

Killer T cells were thought to patrol the body unhindered, freely gaining access to sites of infection. But it seems that, at least in some body tissues, helper T cells must pave the way for killer T-cell entry.

Cytotoxic T lymphocytes (CTLs) are the killer white blood cells of the immune system, having crucial roles in the defence against a range of viral, bacterial and parasitic infections. During microbial colonization at peripheral body sites, such as the outer layers of the skin and mucosal epithelium, circulating CD8+ CTLs (cells that carry a CD8 receptor molecule on their surface) exit from blood vessels to access and destroy cells harbouring pathogens. The CTL response begins in the lymph nodes that drain the infection site, and involves a concerted effort by various immune cells. These include CD4+ helper T cells, which promote optimal CTL expansion and functional programming.

Once armed and released into the bloodstream, CTLs seem to have free access to various non-lymphoid organs1,2. This suggests that the mere presence of these primed killer cells in the circulation might be sufficient for their entry into infected tissues. On page 510 of this issue, Nakanishi et al.3 reveal that this is not the case, or at least not for selected regions of the bodyFootnote 1. The authors describe instead a complex pattern of CTL entry into sites of infection that is orchestrated by the same helper T cells that are involved in the killer cells' initial priming.

To demonstrate this principle, Nakanishi et al.3 used a mouse model of herpes simplex virus (HSV) infection of the vagina, and focused on the infiltration of HSV-specific CTLs into the infected tissue. They show that, as expected4, priming of CTLs is dependent on CD4+ T-cell help. But mucosal invasion by CTLs lagged behind that of helper T cells, suggesting that the helper cells somehow facilitate CTL entry. The authors formally proved this3 by transferring activated CTLs from infected mice into one of two groups of recipients — mice that were deficient in helper T cells or mice that had normal numbers of these cells. The activated CTLs entered rapidly into HSV-infected tissue only in recipient animals that had helper T cells, implicating these latter cells in the control of CTL infiltration.

The authors observed that the helper T cells behave like pioneers, paving the way for CTL entry into the mucosa by altering the local micro-environment. The secreted immune modulator interferon-γ (IFN-γ) was a central mediator of these environmental changes. Crucially, IFN-γ controlled the synthesis of small chemokine molecules by the vaginal epithelium, which guide immune-cell entry into tissues. The specific chemokines involved were CXCL9 and CXCL10 (which bind to the chemokine receptor CXCR3).

Nakanishi et al.3 exclude a role for a regulatory subset of T lymphocytes, known as Foxp3+ CD4+ T cells, in the direct control of CTL migration. However, Foxp3+ cells have been shown5 to promote helper T-cell entry into HSV-infected vaginal tissue and, as a consequence, they could indirectly influence killer T-cell migration.

The authors do not speculate on the mechanism of IFN-γ production by helper T cells, but the most likely scenario involves local recognition of HSV antigen by these cells, which is probably presented by dendritic cells that accumulate under the infected epithelium6. Infiltrating dendritic cells have been implicated in driving helper T-cell activation7 and IFN-γ production8 in non-lymphoid tissues, and thus may be important co-contributors to the complex local immune response that drives optimal CTL recruitment.

Nakanishi and colleagues propose that body tissues can differ in their accessibility to CTLs. For instance, the vagina seems to be restrictive to CTL infiltration, whereas CTLs apparently enter the lung in an unregulated manner3. In humans, HSV also causes skin disease, and studies have described9 sequential T-cell entry into the infected skin similar to that seen in the vaginal tissue. In addition, helper T cells have been shown10 to facilitate CTL recruitment into tumours implanted in the skin. Thus, the skin and its surrounds may be another site in which helper T cells control CTL entry. Further studies are required to determine the generality of Nakanishi and colleagues' findings3, and to define the relative contributions of this helper T-cell-directed migration compared with the innate mechanisms known to promote homeostatic T-cell movement out of blood vessels11.

In the scenario presented by Nakanishi et al.3, helper T cells and killer T cells have inherent differences in their ability to access tissue: migration of CTLs into the site of infection is dependent on CD4+ T-cell help, with the helpers apparently being less restricted in their access. This may reflect differences in their localization within tissues or in the functions of the respective cell populations. For example, helper T cells might remain largely in the submucosal layer of the vagina where they interact with the infiltrating dendritic cells to produce cytokines such as IFN-γ, thereby promoting CTL infiltration. By contrast, CTLs seem to follow the CXCL9/10 gradient, penetrating into the epithelium to actively rid this region of infection (Fig. 1).

Figure 1: Model of assisted entry.
figure1

Nakanishi and colleagues3 studied a mouse model of infection with herpes simplex virus (HSV). They show that CD4+ helper T cells are required to promote entry of CD8+ cytotoxic lymphocytes (CTLs) into infected vaginal tissue. a, Virus-specific helper T cells exit from blood vessels and enter the submucosa of vaginal tissue in response to HSV infection. b, These cells probably recognize antigens presented by the dendritic cells that are known to accumulate in the submucosal layer, and they subsequently secrete the immune-modulator inteferon-γ (IFN-γ). c, In response to IFN-γ, vaginal epithelial cells produce the chemokines CXCL9 and CXCL10. d, These bind to CXCR3 receptors expressed on the surface of CTLs. e, The IFN-γ-induced chemokine gradient ultimately leads to recruitment of CTLs to the infected epithelium, where they eliminate the virus.

It may be possible to exploit Nakanishi and colleagues' findings3 for therapeutic purposes, such as enhancing CTL infiltration of tumours, or inhibiting harmful cell accumulation during autoimmunity. At the very least, their study argues that the simple presence of CTLs in the circulation can no longer be considered a guarantee of their access to peripheral locations for successful infection control. Instead, proof of actual T-cell infiltration is needed.

Notes

  1. 1.

    *This article and the paper under discussion3 were published online on 8 November 2009.

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Gebhardt, T., Carbone, F. A helpers' guide to infection. Nature 462, 418–419 (2009). https://doi.org/10.1038/462418a

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