Willi K. Born

Stimulation of a major subset of lymphocytes expressing T cell receptor γδ by an antigen derived from mycobacterium tuberculosis

Abstract To investigate the possible function(s) of T cell receptor (TcR) γδ expressing lymphocytes, we generated a series of γδ TcR surface positive hybridomas. Spontaneous producers of IL-2 were quite common among these hybridomas, particularly those expressing a certain Vδ gene or gene family (VδM23). Several other experiments indicated that IL-2 production in these hybridomas is triggered via TcR γδ. Surprisingly, every spontaneously reactive γδ + hybridoma was further stimulated by purified protein derivative (PPD) of Mycobacterium tuberculosis, perhaps due to crossreaction with a bacterial antigen homologous to certain eukaryotic heat shock proteins. The finding of an antigen recognized by a γδ TcR could aid in understanding the functional role of the γδ TcR + lymphocytes.

Depletion of a γδ T Cell Subset Can Increase Host Resistance to a Bacterial Infection

γδ T lymphocytes have been shown to regulate immune responses in diverse experimental systems. Because distinct γδ T cell subsets, as defined by the usage of certain TCR V genes, preferentially respond in various diseases and disease models, we have hypothesized that the various γδ T cell subsets carry out different functions. To test this, we compared one particular γδ T cell subset, the Vγ1+ subset, which represents a major γδ T cell type in the lymphoid organs and blood of mice, to other subsets and to γδ T cells as a whole. Using Listeria monocytogenes infection as an infectious disease model, we found that bacterial containment improves in mice depleted of Vγ1+ γδ T cells, albeit mice lacking all γδ T cells are instead impaired in their ability to control Listeria expansion. Our findings indicate that Vγ1+ γδ T cells reduce the ability of the innate immune system to destroy Listeria, even though other γδ T cells as a whole promote clearance of this pathogen.

IL-17-producing gammadelta T cells.

IL‐17 is produced not only by CD4+ αβ T cells, but also CD8+ αβ T cells, NKT cells, and γδ T cells, plus some non‐T cells, including macrophages and neutrophils. The ability of IL‐17 to deploy neutrophils to sites of inflammation imparts this cytokine with a key role in diseases of several types. Surprisingly, γδ T cells are responsible for much of the IL‐17 produced in several disease models, particularly early on.

MHC class I-dependent Vγ4+ pulmonary T cells regulate αβ T cell-independent airway responsiveness

Mice exposed to aerosolized ovalbumin (OVA) develop increased airway responsiveness when deficient in γδ T cells. This finding suggests that γδ T cells function as negative regulators. The regulatory influence of γδ T cells is evident after OVA-sensitization and -challenge, and after OVA-challenge alone, but not in untreated mice. With aerosolized Abs to target pulmonary T cells, we now demonstrate that negative regulation of airway responsiveness is mediated by a small subpopulation of pulmonary γδ T cells. These cells express Vγ4 and depend in their function on the presence of IFN-γ and MHC class I. Moreover, their effect can be demonstrated in the absence of αβ T cells. This novel type of negative regulation seems to precede the development of the adaptive, antigen-specific allergic response.

Alpha beta T-lymphocyte depleted mice, a model for gamma delta T-lymphocyte functional studies.

Adult mice can be depleted of essentially all mature alpha beta T lymphocytes by chronic treatment with the framework-recognizing, pan-specific anti-TCR alpha beta mAb, H57-597. Similar findings have been reported in rats, gamma delta cell populations remain essentially unaltered in size and reactivity. Suppression of alpha beta T-cell development results in the loss of alloantigen reactivity and of B-cell help, suggesting that gamma delta and alpha beta populations differ in their functional capabilities. Indirect effects of the antibody treatment include quantitative changes in splenic B cells, as well as reduced sizes and weights of experimental animals. alpha beta-suppressed mice and rats may provide model systems for studies on gamma delta cell function in vivo.

The role of γδ T lymphocytes in infection

Abstract Many recent studies suggest an involvement of γδ T cells in the immune response to infectious pathogens including viruses, bacteria and eukaryotic parasites. However, it remains unclear whether the responses of γδ T cells are specifically directed against antigens derived from these pathogens or against infection-induced, host-derived ligands.

γδ T cells affect IL-4 production and B-cell tolerance

Significance This study changes our understanding of the relationship between T cells and B cells. Although it is known that T cells provide help for specific B-cell responses, it is unclear if and to what extent T cells also influence preimmune B-cell functions. We show here that γδ T cells modulate systemic antibody levels in nonimmunized mice, including all major subclasses and especially IgE antibodies. One mouse strain deficient in certain γδ T cells developed various autoantibodies, whereas mice deficient in all γδ T cells had relatively normal antibodies. Based on these and other findings, we conclude that γδ T cells, influenced by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance. γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4–producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4–regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4–inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.

γδ T Cells Shape Preimmune Peripheral B Cell Populations

We previously reported that selective ablation of certain γδ T cell subsets, rather than removal of all γδ T cells, strongly affects serum Ab levels in nonimmunized mice. This type of manipulation also changed T cells, including residual γδ T cells, revealing some interdependence of γδ T cell populations. For example, in mice lacking Vγ4+ and Vγ6+ γδ T cells (B6.TCR-Vγ4−/−/6−/−), we observed expanded Vγ1+ cells, which changed in composition and activation and produced more IL-4 upon stimulation in vitro, increased IL-4 production by αβ T cells as well as spontaneous germinal center formation in the spleen, and elevated serum Ig and autoantibodies. We therefore examined B cell populations in this and other γδ-deficient mouse strains. Whereas immature bone marrow B cells remained largely unchanged, peripheral B cells underwent several changes. Specifically, transitional and mature B cells in the spleen of B6.TCR-Vγ4−/−/6−/− mice and other peripheral B cell populations were diminished, most of all splenic marginal zone (MZ) B cells. However, relative frequencies and absolute numbers of Ab-producing cells, as well as serum levels of Abs, IL-4, and BAFF, were increased. Cell transfers confirmed that these changes are directly dependent on the altered γδ T cells in this strain and on their enhanced potential of producing IL-4. Further evidence suggests the possibility of direct interactions between γδ T cells and B cells in the splenic MZ. Taken together, these data demonstrate the capability of γδ T cells of modulating size and productivity of preimmune peripheral B cell populations.

γδ T cells develop, respond and survive – with a little help from CD27

Although the TNF receptor family member CD27 has been known for some time, its functional role as a coreceptor on T and B cells remains poorly understood. Recent reports have shown that CD27 and its ligand CD70 play a critical role in the development and function of γδ T cells in mice. In this issue of the European Journal of Immunology, a study now extends these findings to the Vγ9Vδ2+ subset of human γδ T cells. This subset, whose responses are readily elicited by phosphoantigens, plays an important role in anti‐tumor immune responses. This study shows that most Vγ9Vδ2+ cells express CD27, and signaling via the CD27‐CD70 axis is needed for their survival, proliferation and cytokine secretion. Moreover, CD27 functions as a coreceptor, which promotes, in conjunction with TCR‐mediated signals, expansion of Th1‐biased Vγ9Vδ2+ cells. This new information underscores the significance of CD27 in γδ T‐cell functional differentiation, and is likely to facilitate the development of γδ T‐cell‐based clinical immunotherapy.

γδ T Cells and B Cells

γδ T cells constitute the third arm of a tripartite adaptive immune system in jawed vertebrates, besides αβ T cells and B cells. Like the other two lymphocyte-types, they express diverse antigen receptors, capable of specific ligand recognition. Functionally, γδ T cells represent a system of differentiated subsets, sometimes engaged in cross-regulation, which ultimately determines their effect on other components of the immune system, including B cells and antibodies. γδ T cells are capable of providing help to B cells in antibody production. More recently it became clear that γδ T cells influence B cell differentiation during the peripheral stages of B cell development, control levels of circulating immunoglobulin (all subclasses), and affect production of autoantibodies. Because of this relationship between γδ T cells and B cells, the extensive variation of γδ T cells among human individuals might be expected to modulate their humoral responsiveness.