## 1 Introduction
### The Hybrid \(\alpha\beta\gamma\delta\) T Cells  
The immunological dogma is that conventional \(\alpha\beta\) and \(\gamma\delta\) T cells originate from common precursors in the thymus, then develop into cells expressing either \(\alpha\beta\) or \(\gamma\delta\) TCR and occupy a specific and highly conserved niche within the immune system. The mechanisms underlying the divergence and lineage fate are not completely defined. Expression of aberrant TCR chains has been demonstrated among \(\alpha\beta\) and \(\gamma\delta\) T cell populations in mice [30; 31; 32]. For example, in-frame TCR \(\delta\) rearrangements have been identified in \(\alpha\beta\) T cells [33], and functional TCR \(\beta\) rearrangements have been detected in \(\gamma\delta\) T cells [34]. Such aberrant TCR chain expression in mice may be explained by the fact that (i) the murine TCR \(\alpha\)/\(\delta\) locus co-expresses \(\alpha\) and \(\delta\) TCR, thus implying productive rearrangement of TCR \(\alpha\) and TCR \(\delta\) on different alleles, and (ii) the TCR \(\gamma\) locus is repeatedly duplicated which may result in multiple rearrangements. [PERSON] et al. characterized a population of human T cells, named \(\delta\)/\(\alpha\beta\) T cells, expressing TCRs comprised of a TCR-\(\delta\) variable gene (V81) fused to joining \(\alpha\) and constant \(\alpha\) domains, paired with an array of TCR-\(\beta\) chains. They demonstrated that these cells, which represent \(\approx\)50% of all V81+ human T cells, can recognize peptide- and lipid-based antigens presented by human leukocyte antigen (HLA) and CD1d, respectively [35]. Intriguingly, [PERSON] et al. documented a population of V81+CD4+ \(\gamma\delta\) T cells expressing stem cell and progenitor markers, i.e., CD34 and CD38, that are able to develop into functional \(\alpha\beta\) T cells. The route taken by this process involves the re-organization of the V81+ \(\gamma\delta\) TCR into the \(\alpha\beta\) TCR, as a consequence of TCR-\(\gamma\) chain downregulation and the expression of surface V81+V8+ TCR components. The authors monitored TCR changes in V81+CD4+ clones and observed that, under inflammatory stimuli, these cells downregulated the TCR-\(\gamma\) and TCR-\(\delta\) chains and simultaneously rearranged TRBV and TRAV segments. Such trans-differentiation process was readily detectable in vivo in inflamed tissue providing a conceptual framework for extrthymic T cell development. Thus, the \(\alpha\beta\) T cells reconstituted with this mechanism may be unable to induce GvHD, since they acquire a \"self-education\" [36]. Interestingly, [PERSON] et al. reported that the key signature protein of proteotype \(\gamma\delta\) T cells in transplanted patients treated with ZOL [37], is Bloom (BLM), which is important in development, maintenance, and function of \(\alpha\beta\) T lymphocytes [38]. Mutations in _BLM_ are responsible for Bloom Syndrome, a disorder characterized by immunodeficiency and propensity to develop cancer. The essential role of BLM in early \(\alpha\beta\) T cell differentiation was evidenced by the impairment of T cell differentiation, proliferation, and response to antigens in BLM-deficient mice. Thus, in addition to the fact that ZOL increased the V51 percentage and induced BLM in \(\gamma\delta\) T cells [37], ZOL may induce a'reservoir' of \(\alpha\beta\) T cell progenitors for the development of \(\alpha\beta\) T cells in vivo. Very recently, [PERSON] et al. identified a discrete population of T cells that coexpressed \(\alpha\beta\) and \(\gamma\delta\) TCRs. These hybrid \(\alpha\beta\)-\(\gamma\delta\) T cells were transcriptionally distinct from conventional \(\gamma\delta\) T cells, poised to migrate to sites of inflammation, and were responsive to MHC class I/II-restricted peptide antigens or to stimulation with IL-1\(\beta\) and IL-23.