ReviewA comprehensive review of the phenotype and function of antigen-specific immunoregulatory double negative T cells
Highlights
► Immunoregulatory DN T cells present a unique antigen-specific mode of tolerance. ► A major challenge remains the identification of unique markers for these cells. ► Human DN T cells present a promising avenue in cell therapy.
Introduction
Immune tolerance is dependent on the immune system discriminating between self and non-self. A break in immune tolerance results in autoimmunity, which can lead to the destruction of healthy organs, glands, joints or the central nervous system. The triggers that cause T or B lymphocytes to aberrantly recognize and mount an immune response against self-antigens remain to be fully elucidated. However, a prominent role in the generation and maintenance of immune tolerance has been attributed to the number and function of regulatory cell subsets. Indeed, several populations belonging to the T cell or B cell compartment carry the ability to inhibit inadequate immune response and promote peripheral tolerance, including CD4+CD25+FoxP3+ naturally occurring T cells (Tregs), IL-10-producing CD4+ Tr1 cells, TGF-β-producing CD4+ Th3 cells, CD8+CD28− T cells, CD4−CD8− (DN, double negative) T cells, CD4+CD8+ (DP, double positive) T cells, and Natural Killer-like T (NKT) cells [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], as well as B10 regulatory B cells [11], [12]. These various regulatory cell populations express diverse mechanisms of action, which may also vary depending on the experimental model being studied [2], suggesting that the contribution to immune tolerance, as well as to disease prevention, differ amongst these various cell populations. Here, we will present a comprehensive review of the literature on one of these regulatory T cell populations, namely DN T cells, which have been studied in both mice and humans for their contribution to peripheral tolerance, disease prevention and their potential for use in cellular therapy.
Section snippets
Challenge associated with the specific identification of immunoregulatory DN T cells
CD4−CD8− T cells are defined by exclusion (i.e., as CD3+ non-CD4 non-CD8 T cells) and, as a consequence, the term refers to three T cell populations that are infrequent in the peripheral blood and lymphoid organs, including γδ T cells [13], [14], a subset of NKT cells [15], and DN T cells [16]. As a result, other markers besides CD4, CD8, and CD3 must be used in order to distinguish these three subsets (see Table 1). The expression of the γδ T cell receptor (TCR) separates γδ T cells from both
DN T cell phenotype
Immunoregulatory DN T cells compose approximately 1–3% of total T cells in non-transgenic mice [39], [40], [41] and in humans [26] making them difficult to isolate and subsequently study. For this reason, as well as those noted above, DN T cells have been mostly investigated in TCR transgenic mice, where the insertion of various αβTCR transgenes increases the proportion of immunoregulatory DN T cells in the lymphoid organs of mice, as observed in the HY-TCR, the 4E3-TCR, the 1H3.1, the 2C TCR
The immunoregulatory function of TCR transgenic DN T cells is antigen-specific
The functional properties of DN T cells have been mainly studied using the 2C TCR transgenic mouse model, which is an MHC class I-restricted model where the DN T cells express the transgenic αβTCR heterodimer as detected by the 1B2 anti-2C clonotypic monoclonal antibody (mAb) [71]. Using this model, 2C DN T cells were shown to suppress the proliferation and cytotoxic activity of 2C TCR transgenic CD8+ T cells in vitro, but not of CD8+ T cells carrying other antigen specificities [16], [45], [72]
In vivo function of immunoregulatory DN T cells
Although the literature for the in vitro function of DN T cells is vast, publications on the in vivo function of DN T cells are quite sparse. Indeed, using non-transgenic DN T cells, a single study has confirmed a targeted population in vivo, namely B lymphocytes. Ma, Y and colleagues [91] used a cardiac xenotransplantation model to verify whether DN T cell transfer, in addition to treatment with an immunosuppressive reagent, could ameliorate graft survival. Importantly, the transfer of
Conclusion
The observations made using both TCR transgenic and non-transgenic systems have demonstrated that DN T cells may be of particular interest for cellular therapy due to their ability to eliminate various cellular targets in an antigen-specific manner (Fig. 1a and b). Yet, despite the discovery of numerous DN T cell targets using both transgenic and non-transgenic models, only B cells have been confirmed as targets of DN T cells in vivo [91]. Thus, there is a clear lack of in vivo data to validate
Acknowledgements
EEH is a recipient of a CIHR PhD scholarship and Diabete Quebec Award, SL holds a CIHR New Investigator scholarship. SL is funded by the Foundation of the Maisonneuve-Rosemont Hospital, the Canadian Foundation for Innovation and the Natural Sciences and Engineering Research Council of Canada.
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