γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends.

Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

Preconceptional Immunization Can Modulate Offspring Intrathymic IL-17-Producing γδT Cells with Epigenetic Implications Mediated by microRNAs.

The mechanisms through which maternal immunization can modulate offspring thymic maturation of lymphocytes are not fully understood. Here, we aimed to evaluate whether maternal OVA-immunization can inhibit the maturation of IL-17-producing γδT cells in offspring thymus, and if this mechanism has epigenetic implications mediated by microRNAs (miRNAs) expression. Wild-type (WT) C57BL/6 females were immunized with OVA in Alum or Alum alone and were mated with normal WT males. Evaluating their offspring thymus at 3 or 20 days old (d.o.), we observed that maternal OVA immunization could inhibit the thymic frequency of offspring CD27- and IL-17+ γδT cells at the neonatal and until 20 days old. Furthermore, we evaluated the expression of function-related γ and δ variable γδTCR chains (Vγ1, Vγ2, Vγ3, Vδ4, and Vδ6.3), observing that maternal OVA-immunization inhibits Vγ2 chains expression. The small RNAs (sRNAs), particularly miRNAs, and messenger RNAs (mRNA) expression profiles by pools of thymus tissue samples (from 9 to 11 mice) from offspring OVA-immunized or Alum-immunized mothers were analyzed via Illumina sequencing platform and bioinformatics approaches. Using a fold change >4, our results showed that seven miRNAs (mmu-miR-126a-3p, 101a-3p, 744-3p,142-5p, 15a-5p, 532-5p, and 98-5p) were differentially expressed between both groups. Ten target genes were predicted to interact with the seven selected miRNAs. There were no enriched categories of gene ontology functional annotation and pathway enrichment analysis for the target genes. Interestingly, four of the identified miRNAs (mmu-miR-15a, mmu-miR-101 mmu-miR-126, and mmu-miR-142) are related to IL-17 production. Our data is of significance because we demonstrate that maternal immunization can modulate offspring thymic maturation of IL-17-producing γδT cells possibly by an epigenetic mechanism mediated by miRNAs.

Special features of γδ T cells in ruminants

Ruminant γδ T cells were discovered in the mid-1980′s shortly after a novel T cell receptor (TCR) gene from murine cells was described in 1984 and the murine TCRγ gene locus in 1985. It was possible to identify γδ T cell populations early in ruminants because they represent a large proportion of the peripheral blood mononuclear cells (PBMC). This null cell population, γδ T cells, was designated as such by its non-reactivity with monoclonal antibodies (mAb) against ovine and bovine CD4, CD8 and surface immunoglobulin (Ig). γδ T cells are non-conventional T cells known as innate-like cells capable of using both TCR as well as other types of receptor systems including pattern recognition receptors (PRR) and natural killer receptors (NKR). Bovine γδ T cells have been shown to respond to stimulation through toll-like receptors, NOD, and NKG2D as well as to cytokines alone, protein and non-protein antigens through their TCR, and to pathogen-infected host cells. The two main populations of γδ T cells are distinguished by the presence or absence of the hybrid co-receptor/PRR known as WC1 or T19. These two populations not only differ by their proportional representation in various tissues and organs but also by their migration into inflamed tissues. The WC1+ cells are found in the blood, skin and spleen while the WC1− γδ T cells predominate in the gut, mammary gland and uterus. In ruminants, γδ T cells may produce IFNγ, IL-17, IL-10 and TGFβ, have cytotoxic activity and memory responses. The expression of particular WC1 family members controls the response to particular pathogens and correlates with differences in cytokine responses. The comparison of the WC1 gene families in cattle, sheep and goats is discussed relative to other multigenic arrays that differentiate γδ T cells by function in humans and mice.