Allergic airway inflammation and hyperreactivity are modulated by γδ T cells, but different experimental parameters can influence the effects observed. For example, in sensitized C57BL/6 and BALB/c mice, transient depletion of all TCR-δ+ cells just before airway challenge resulted in airway hyperresponsiveness (AHR), but caused hyporesponsiveness when initiated before i.p. sensitization. Vγ4+ γδ T cells strongly suppressed AHR; their depletion relieved suppression when initiated before challenge, but not before sensitization, and they suppressed AHR when transferred before challenge into sensitized TCR-Vγ4−/−/6−/− mice. In contrast, Vγ1+ γδ T cells enhanced AHR and airway inflammation. In normal mice (C57BL/6 and BALB/c), enhancement of AHR was abrogated only when these cells were depleted before sensitization, but not before challenge, and with regard to airway inflammation, this effect was limited to C57BL/6 mice. However, Vγ1+ γδ T cells enhanced AHR when transferred before challenge into sensitized B6.TCR-δ−/− mice. In this study Vγ1+ cells also increased levels of Th2 cytokines in the airways and, to a lesser extent, lung eosinophil numbers. Thus, Vγ4+ cells suppress AHR, and Vγ1+ cells enhance AHR and airway inflammation under defined experimental conditions. These findings show how γδ T cells can be both inhibitors and enhancers of AHR and airway inflammation, and they provide further support for the hypothesis that TCR expression and function cosegregate in γδ T cells.

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The V gamma 6/V delta 1(+) cells, the second murine gamma delta T cell subset to arise in the thymus, express a nearly invariant T cell receptor (TCR), colonize select tissues, and expand preferentially in other tissues during inflammation. These cells are thought to help in regulating the inflammatory response. Until now, V gamma 6/V delta 1(+) cells have only been detectable indirectly, by expression of V gamma 6-encoding mRNA. Here, we report that 17D1, a monoclonal antibody, which detects the related epidermis-associated V gamma 5/V delta 1(+) TCR, will also bind the V gamma 6/V delta 1(+) cells if their TCR is first complexed to an anti-C delta antibody. Features of this special condition for recognition suggest the possibility that an alternate structure exists for the V gamma 6/V delta 1 TCR, which is stabilized upon binding to the anti-C delta antibody. Using the 17D1 antibody as means to track this gamma delta T cell subset by flow cytometry, we discovered that the response of V gamma 6/V delta 1(+) cells during inflammation often far exceeds that of other subsets and that the responding V gamma 6/V delta 1(+) cells display a strikingly uniform activation/memory phenotype compared with other gamma delta T cell subsets.

The gammadelta T-cell receptors (TCRs) are limited in their diversity, suggesting that their natural ligands may be few in number. Ligands for gammadeltaTCRs that have thus far been determined are predominantly of host rather than foreign origin. Correlations have been noted between the Vgamma and/or Vdelta genes a gammadelta T cell expresses and its functional role. The reason for these correlations is not yet known, but several different mechanisms are conceivable. One possibility is that interactions between particular TCR-V domains and ligands determine function or functional development. However, a recent study showed that at least for one ligand, receptor specificity is determined by the complementarity-determining region 3 (CDR3) component of the TCR-delta chain, regardless of the Vgamma and/or Vdelta. To determine what is required in the TCR for other specificities and to test whether recognition of certain ligands is connected to cell function, more gammadeltaTCR ligands must be defined. The use of recombinant soluble versions of gammadeltaTCRs appears to be a promising approach to finding new ligands, and recent results using this method are reviewed.

The Vγ4+ pulmonary subset of γδ T cells regulates innate airway responsiveness in the absence of αβ T cells. We now have examined the same subset in a model of allergic airway disease, OVA-sensitized and challenged mice that exhibit Th2 responses, pulmonary inflammation, and airway hyperreactivity (AHR). In sensitized mice, Vγ4+ cells preferentially increased in number following airway challenge. Depletion of Vγ4+ cells before the challenge substantially increased AHR in these mice, but had no effect on airway responsiveness in normal, nonchallenged mice. Depletion of Vγ1+ cells had no effect on AHR, and depletion of all TCR-δ+ cells was no more effective than depletion of Vγ4+ cells alone. Adoptively transferred pulmonary lymphocytes containing Vγ4+ cells inhibited AHR, but lost this ability when Vγ4+ cells were depleted, indicating that these cells actively suppress AHR. Eosinophilic infiltration of the lung and airways, or goblet cell hyperplasia, was not affected by depletion of Vγ4+ cells, although cytokine-producing αβ T cells in the lung increased. These findings establish Vγ4+ γδ T cells as negative regulators of AHR and show that their regulatory effect bypasses much of the allergic inflammatory response coincident with AHR.

It has been reported that the IgE response to allergens is influenced by γδ T cells. Intrigued by a study showing that airway challenge of mice with OVA induces in the spleen the development of γδ T cells that suppress the primary IgE response to i.p.-injected OVA-alum, we investigated the γδ T cells involved. We found that the induced IgE suppressors are contained within the Vγ4+ subset of γδ T cells of the spleen, that they express Vδ5 and CD8, and that they depend on IFN-γ for their function. However, we also found that normal nonchallenged mice harbor IgE-enhancing γδ T cells, which are contained within the larger Vγ1+ subset of the spleen. In cell transfer experiments, airway challenge of the donors was required to induce the IgE suppressors among the Vγ4+ cells. Moreover, this challenge simultaneously turned off the IgE enhancers among the Vγ1+ cells. Thus, airway allergen challenge differentially affects two distinct subsets of γδ T cells with nonoverlapping functional potentials, and the outcome is IgE suppression.

Pulmonary gammadelta T cells protect the lung and its functions, but little is known about their distribution in this organ and their relationship to other pulmonary cells. We now show that gammadelta and alphabeta T cells are distributed differently in the normal mouse lung. The gammadelta T cells have a bias for nonalveolar locations, with the exception of the airway mucosa. Subsets of gammadelta T cells exhibit further variation in their tissue localization. gammadelta and alphabeta T cells frequently contact other leukocytes, but they favor different cell-types. The gammadelta T cells show an intrinsic preference for F4/80+ and major histocompatibility complex class II+ leukocytes. Leukocytes expressing these markers include macrophages and dendritic cells, known to function as sentinels of airways and lung tissues. The continuous interaction of gammadelta T cells with these sentinels likely is related to their protective role.

In the last two decades, it has become clear that cd T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, cd antigens as a whole resemble more the antigens recognized by antibodies than those recognized by ab T cells. Because of this antigenic diversity, no single mechanism-such as the major histocompatibility complex (MHC) restriction of ab T cells-is likely to provide a basis for all observed T-cell antigen receptor (TCR)-dependent cd T-cell responses. Furthermore, available evidence suggests that many individual cd T cells are poly-specific, probably using different modes of ligand recognition in their responses to unrelated antigens. While posing a unique challenge in the maintenance of self-tolerance, this broad reactivity pattern might enable multiple overlapping uses of cd T-cell populations, and thus generate a more efficient immune response.