A Distinctive γδ T Cell Repertoire in NOD Mice Weakens Immune Regulation and Favors Diabetic Disease.

Previous studies in mice and humans suggesting that T cells play a role in the development of type 1 diabetes have been inconsistent and contradictory. We attempted to resolve this for the type 1 diabetes-prone NOD mice by characterizing their T cell populations, and by investigating the functional contributions of particular T cells subsets, using V-gene targeted NOD mice. We found evidence that NOD V4+ T cells inhibit the development of diabetes, and that the process by which they do so involves IL-17 production and/or promotion of regulatory CD4+ αβ T cells (Tregs) in the pancreatic lymph nodes.

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.

γδ T cells affect IL-4 production 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.

γδ T cells recognize the insulin B:9-23 peptide antigen when it is dimerized through thiol oxidation.

The insulin peptide B:9-23 is a natural antigen in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). In addition to αβ T cells and B cells, γδ T cells recognize the peptide and infiltrate the pancreatic islets where the peptide is produced within β cells. The peptide contains a cysteine in position 19 (Cys19), which is required for the γδ but not the αβ T cell response, and a tyrosine in position 16 (Tyr16), which is required for both.

Antigen-specific regulation of IgE antibodies by non-antigen-specific γδ T cells.

We re-examined the observation that γδ T cells, when transferred from mice tolerized to an inhaled conventional Ag, suppress the allergic IgE response to this Ag specifically. Using OVA and hen egg lysozyme in crisscross fashion, we confirmed the Ag-specific IgE-regulatory effect of the γδ T cells. Although only Vγ4(+) γδ T cells are regulators, the Ag specificity does not stem from specificity of their γδ TCRs.

A canonical Vγ4Vδ4+ γδ T cell population with distinct stimulation requirements which promotes the Th17 response.

We previously reported a subset of γδ T cells in mice which preferentially responds following intradermal immunization with collagen in complete Freund's adjuvant (CFA). These cells express a nearly invariant "canonical" Vγ4Vδ4+ TCR. They are potent producers of IL-17A and promote the development of collagen-induced arthritis.

αβ TCR⁺ T cells, but not B cells, promote autoimmune keratitis in b10 mice lacking γδ T cells.

Purpose: To investigate additional factors in the spontaneous development of keratitis previously reported in B10.TCRδ⁻/⁻ female mice.

Methods: The study tested whether susceptible B10.

Peptide antigens for gamma/delta T cells.

γδ T cells express adaptive antigen receptors encoded by rearranging genes. Their diversity is highest in the small region of TCR V-J junctions, especially in the δ chain, which should enable the γδ TCRs to distinguish differences in small epitopes. Indeed, recognition of small molecules, and of an epitope on a larger protein has been reported.

The influence of IgE-enhancing and IgE-suppressive gammadelta T cells changes with exposure to inhaled ovalbumin.

It has been reported that the IgE response to allergens is influenced by gammadelta T cells. Intrigued by a study showing that airway challenge of mice with OVA induces in the spleen the development of gammadelta T cells that suppress the primary IgE response to i.p.

Allergic airway hyperresponsiveness-enhancing gammadelta T cells develop in normal untreated mice and fail to produce IL-4/13, unlike Th2 and NKT cells.

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory gammadelta T cells. The AHR-enhancing cells belong to the Vgamma1(+) gammadelta T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR.

Protective role of gammadelta T cells in spontaneous ocular inflammation.

Purpose: A role for gammadelta T cells in immunoregulation has been shown in a number of studies, but in the absence of infection or induced disease, mice lacking gammadelta T cells generally appear to be healthy. That certain mice lacking gammadelta T cells often spontaneously develop keratitis, characterized by a progressive and destructive inflammation of the cornea is reported here.

Methods: The keratitis developing in these mice was characterized in terms of prevalence in males versus females, age of onset, and histologic features.

Macrophages express multiple ligands for gammadelta TCRs.

As only a handful of ligands have been identified, the general nature of the ligands recognized by gammadelta T cells remains unresolved. In this study, soluble multimerized gammadelta T cell receptors (smTCRs) representing the TCRs of two gammadelta T cell subsets common in the mouse were used to detect and track their own ligands. Ligands for both subsets were found on resident peritoneal macrophages taken from untreated mice, and the expression of both was further induced by Listeria monocytogenes infection.

Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells.

Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred gammadelta T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vgamma1+Vdelta5+ gammadelta T cells enhanced AHR.

gammadelta T lymphocytes-selectable cells within the innate system?

Lymphocytes expressing gammadelta T cell receptors (TCR) constitute an entire system of functionally specialized subsets that have been implicated in the regulation of immune responses, including responses to pathogens and allergens, and in tissue repair. The gammadelta TCRs share structural features with adaptive receptors and peripheral selection of gammadelta T cells occurs. Nevertheless, their specificities may be primarily directed at self-determinants, and the responses of gammadelta T cells exhibit innate characteristics.

gammadelta T-cell receptors: functional correlations.

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.

Distribution and leukocyte contacts of gammadelta T cells in the lung.

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.

Aerosolized anti-T-cell-receptor antibodies are effective against airway inflammation and hyperreactivity.

Aerosolized monoclonal antibodies (mAbs) specific for T-cell receptors (TCR) were used to manipulate T-cell function in airways of ovalbumin (OVA)-sensitized and -challenged mice with airway hyperresponsiveness (AHR). The inhaled mAbs were found to be effective at low doses, had little or no systemic effect and specifically abrogated both effector and regulatory functions of the targeted T cells. Specific mAbs targeting alphabeta T cells suppressed and those targeting gammadelta T cells enhanced AHR.

Detection of cell surface ligands for the gamma delta TCR using soluble TCRs.

The natural ligands recognized by gammadelta TCRs are still largely unknown, in part because immunization does not normally result in Ag-specific gammadelta T cell responses. Taking advantage of an established ligand for a particular gammadelta TCR, we demonstrated that a multimerized recombinant form of this gammadelta TCR can be used like a mAb to specifically detect its own ligand. Using the same approach for more common gammadelta TCRs whose ligands remain unknown, we detected on certain cell lines molecules that appear to be ligands for three additional gammadelta TCRs.

Different potentials of gamma delta T cell subsets in regulating airway responsiveness: V gamma 1+ cells, but not V gamma 4+ cells, promote airway hyperreactivity, Th2 cytokines, and airway inflammation.

Allergic airway inflammation and hyperreactivity are modulated by gammadelta 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-delta(+) cells just before airway challenge resulted in airway hyperresponsiveness (AHR), but caused hyporesponsiveness when initiated before i.p.

Subset-specific, uniform activation among V gamma 6/V delta 1+ gamma delta T cells elicited by inflammation.

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.

V gamma 4+ gamma delta T cells regulate airway hyperreactivity to methacholine in ovalbumin-sensitized and challenged mice.

The Vgamma4(+) pulmonary subset of gammadelta T cells regulates innate airway responsiveness in the absence of alphabeta 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, Vgamma4(+) cells preferentially increased in number following airway challenge.

Effect of microbial heat shock proteins on airway inflammation and hyperresponsiveness.

Microbial heat shock proteins (hsp) have been associated with the generation and induction of Th1-type immune responses. We tested the effects of treatment with five different microbial hsp (Mycobacterium leprae, Streptococcus pneumoniae, Helicobacter pylori, bacillus Calmette-Guérin, and Mycobacterium tuberculosis) in a murine model of allergic airway inflammation and airway hyperresponsiveness (AHR). Mice were sensitized to OVA by i.

MHC class I-dependent Vgamma4+ pulmonary T cells regulate alpha beta T cell-independent airway responsiveness.

Mice exposed to aerosolized ovalbumin (OVA) develop increased airway responsiveness when deficient in gammadelta T cells. This finding suggests that gammadelta T cells function as negative regulators. The regulatory influence of gammadelta T cells is evident after OVA-sensitization and -challenge, and after OVA-challenge alone, but not in untreated mice.