Thymic maturation determines γδ T cell function, but not their antigen specificities

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γδ T cells contribute uniquely to host immune defense, but how they do so remains unclear. Recent work suggests that thymic selection does little to constrain γδ T cell antigen specificities, but instead determines their effector fate. When triggered through the T cell receptor, ligand-experienced cells make IFNγ, whereas ligand-naïve γδ T cells produce IL-17, a major initiator of inflammation. These advances warrant a fresh look at how γδ T cells may function in the immune system.

Introduction

γδ T cells, like αβ T cells, develop in the thymus before entering the periphery. In the case of αβ T cells, thymic development entails endogenous ligand-driven positive and negative selections, which determine what αβ T cell can recognize and whether these T cells will develop into CD4+ helper or CD8+ cytolytic T cells. However, the role of ligand-mediated selection in γδ T cell development and function has been less clear. In the past year this issue has been re-examined, and the emerging picture is fundamentally different from what we know about αβ T cell development and differentiation. Encountering ligand in the thymus is not required for γδ T cells to mature and exit to the periphery, and antigen naïve γδ T cells appear to constitute a large fraction of the peripheral repertoire. Furthermore, regardless of antigen experience, γδ T cells can be triggered to produce cytokines without requirement for antigen-specific priming. Importantly, antigen naïve γδ T cells make IL-17. In this review, we will discuss these recent findings and their implications.

Section snippets

The development of γδ T cells with invariant TCRs

Murine γδ T cells can be divided into two categories on the basis of their receptor diversity, ontogeny and anatomical location. The first group of the invariant γδ T cells is generated from the first two waves of T cells in the fetal thymus and later found in either the epidermis of the skin, or the epithelium of the reproductive tract. The first wave produces the skin resident dendritic epidermal T cells (DETCs), which express Vγ5 and Vδ1 TCRs [1], whereas the second wave produces the γδ T

Encountering thymic ligand is neither required, nor inhibitory for the generation of antigen-specific γδ T cells in adult animals

The second group of γδ T cells appears postnatally after the first two waves of fetal γδ thymocyte development. Unlike the invariant γδ T cells, this group expresses TCRs with various Vδs and Vγs, and diverse CDR3 regions. In adult mice, these cells are found in all secondary lymphoid organs and below the epithelium or mucosal surfaces of many tissues, including the small intestine and lung. Only a few ligands have been identified for these cells, which include both host-derived and

A large fraction of lymphoid γδ T cells may not have encountered ligand during development or in the periphery

T10/T22-specific γδ T cells that developed in B6, BALB/c, and B2m−/− mice are similar in number, but phenotypically different, leading to several insights. First, it was obvious that the majority of T10/T22-specific γδ T cells from B6 and BALB/c mice have encountered antigen whereas those from the B2m−/− mice have not. In particular, T10/T22-specific cells from B6 and BALB/c mice expressed higher levels of the IL-2 and IL-15 receptor common β chain (CD122) than those from B2m−/− mice (Figure 1

Antigen naïve γδ T cells make IL-17 without requirement for antigen-specific priming

Jensen et al. found that upon stimulation through the TCR, CD122lo cells make IL-17, and CD122hi γδ T cells make IFNγ. The ability to differentially make IL-17 versus IFNγ can be observed in γδ T cells from the spleen, lymph nodes [16••], and peritoneal cavity [22•]. Importantly, CD122lo γδ T cells have already gained the ability to make IL-17 in the thymus [16••, 22•]. One exception is in the interepithelial lymphocyte (IEL) compartment of the small intestine, where γδ IELs are mainly CD122lo,

Conclusion

Whether or not the development of T10/T22-specific γδ T cells is typical of the entire adult γδ T cell repertoire will require further studies when additional γδ T cell antigens are identified. Until then, these recent developments seem to indicate that γδ T cells differ from αβ T cells in how thymic development influences their TCR specificities and effector-fate development. In particular, the absence of positive selection, and the lack of antigen-specific priming, seems ideal for γδ T cells

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank our numerous collaborators, and past and present laboratory members for contributions and stimulating discussions on this subject. We also thank MM Davis for critically reading this manuscript. KJ was supported by the Stanford Graduate Fellowship (SGF) and the National Institutes of Health (NIH) Cell and Molecular Biology (CMB) training grant. This work was supported by grants A1 33431 and U19 AI 057229 from the NIH (YC).

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