The immune system's capacity to regulate its own activities can be exploited to prevent rejection of transplanted organs and to reverse autoimmune diseases such as diabetes. The chief agents of this immune self-regulation system are specialized cells — T regulatory cells (Treg) — that somehow prevent other immune cells from attacking healthy tissues. In this issue (page 997)1, Lu et al.1 demonstrate that the protective actions of Treg cells depend on so-called mast cells, which were hitherto bad-mouthed for their undesirable role in allergic responses. Perhaps, at last, a virtuous physiological role for mast cells has been uncovered.

Long-term tolerance of transplanted tissues by the body can be achieved by using a short treatment of antibodies that block vital co-receptors (CD4 and CD8) or co-stimulatory molecules (CD154) on a subset of immune cells (T cells). This reprogramming of the immune system depends on the activity of specialized regulatory CD4+ T cells (Treg) that are drawn to the transplanted tissue and its surrounding milieu. The Treg cells confer on the tissue some special exemption from attack, just as the fetus in the womb is protected from the mother's immune system. A major goal of current immunological research is to establish just how Treg cells ensure this ceasefire.

A clue to what that mechanism is came from the observation that cultures of Treg cells tend to be contaminated with 'unwanted' mast cells2. This was attributed to a secreted molecule called IL-9 that is made by the Treg cells and that enhances mast cell growth and functionality. More surprisingly, when recipient mice that were tolerating a skin graft were given a second graft from an identical donor, the second graft became infiltrated not only with Treg cells, but also with mast cells3. This led to the proposal that Treg and mast cells might form a functional unit that mediates graft tolerance2,3.

Lu et al.1 confirm these findings and extend them by performing crucial work using an experimental mouse strain (C57BL/6–KitW-sh/KitW-sh) that is genetically engineered to be deficient in mast cells4. The authors used these mice as recipients for transplants, but their attempts to induce therapeutic tolerance in the mice were unsuccessful, as all the test grafts were promptly rejected. Spectacularly, however, injecting mast-cell-enriched cell cultures into the recipient mice restored the host's capacity to accept grafts for prolonged periods.

The second major breakthrough by Lu et al.1 comes from the discoveries that all categories of Treg cell make IL-9, that IL-9 can be found in the tolerated graft, and that neutralization of IL-9 in vivo prevents regulation of graft rejection by Treg cells. The authors interpret the findings as indicating that IL-9 from Treg cells is involved in the recruitment and activation of mast cells at the graft site.

Mast cells belong to the 'innate' immune system — the system that provides immediate defence against microbes that the body hasn't encountered before. Although they participate in immune responses, they do not intrinsically recognize unique antigens. The recognition of specific antigens is mediated instead by the 'adaptive' immune system, where cells such as T cells remember previous microbe encounters and react strongly against the aliens if the infection is repeated.

When it comes to immunity towards microbes, cells of the innate immune system, including mast cells, macrophages and dendritic cells, interact with the adaptive system in two ways. First, they sense dangerous microbes through generic receptors for potential pathogens, and, once activated, they alert the adaptive system to the danger. Mast cells, for instance, expel packets of mediator molecules (including histamine) that cause an immediate inflammatory reaction and attract adaptive cells. Second, innate immune cells can act as the executive arm of the adaptive system, once armed with antibodies or mobilized to killer-mode by T-cell-derived mediators.

Recent research on macrophages and dendritic cells has taught us that the innate immune system may also mediate the opposing process of permanently decommissioning adaptive cells so that they cannot mount an immune response. For example, immature dendritic cells display antigens in a way that makes T cells tolerate that antigen so they no longer respond to it. Moreover, Treg cells can manifest their suppressive activity by modulating dendritic cells, so that the dendritic cells are no longer able to alert the adaptive cells to danger.

Perhaps this symmetry — in both activating and inhibiting adaptive reactions — is a general feature of innate cells. We have tended to think of these cells as agents of destruction, waiting around until the microbe appears. Now, there are reasonable grounds for elevating their status to cells that have a positive physiological role — ensuring self-tolerance and/or tissue integrity through the maintenance of 'privileged' microenvironments where adaptive immune responses are damped down (Fig. 1).

Figure 1: Immune self-regulation: a possible mechanism.
figure 1

The work of Lu et al.1 suggests that mast cells interact with regulatory T cells (Treg) to exempt transplanted tissues from immune response. If sufficient Treg cells can enter a transplanted tissue, they could then mobilize mast cells to enhance the capacity of the mast cells to decommission immune responses within a limited 'privileged' area. By interacting with antigen in the tissue, the Treg cells are activated to produce the IL-9 polypeptide and perhaps other molecules (maybe IL-10 or TGF-β). These molecules enable Treg cells to interact with cells of the innate immune system (such as dendritic cells or macrophages), leading to further inhibition of immune responses. The end result is that T cells, which might otherwise kill other cells and damage tissues, are prevented from doing so and are then inactivated.

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The implications of the Lu et al.1 paper go beyond transplantation. This work could form the basis for understanding why mast cells are located in very specific sites within tissues (for example, nerves, vessels, hair follicles or epithelia). It was always hard to see how this positioning was related to their potential for immune function. Perhaps these sites require some low-level immune privilege. Also, is it possible that the mast cells found within tumours contribute some immune privilege? In support of this idea, mast-cell-deficient mice seem to have some natural resistance to the induction of tumours5.

Which checkpoint of the immune self-regulatory response needs the mast cells is not yet established. Are they required to induce T cells to a regulatory role or are they required at some later phase in the execution of that function? Either way, the current findings will galvanize research into the molecular basis by which mast cells decommission immune function, and provide a possible new direction for acquiring drug targets.Footnote 1