Partial and Ineffective Activation of Vγ9Vδ2 T Cells by Mycobacterium tuberculosis-Infected Dendritic Cells

Abstract

γδ T cells and dendritic cells (DCs) participate in early phases of immune response against Mycobacterium tuberculosis. We investigated whether a close functional relationship exists between these two cell populations using an in vitro coculture in a human system. Vγ9Vδ2 T cells induce full maturation of M. tuberculosis-infected immature DCs, as demonstrated by upregulation of the costimulatory CD80, CD86, CD40, and HLA-DR molecules on infected DCs after 24 h of coculture. Reciprocally, infected DCs induced substantial activation of Vγ9Vδ2 T cells upon coculture, which was cell-to-cell contact and TCR dependent, as demonstrated in transwell experiments. However, infected DCs selectively induced proliferative, but not cytokine or cytolytic, responses of Vγ9Vδ2 T cells, and this was associated with the expansion of phenotypically immature, central memory-type Vγ9Vδ2 T cells. Importantly, expansion of central memory Vγ9Vδ2 T cells and reduction of the pool of Vγ9Vδ2 T cells with immediate effector functions (effector memory and terminally differentiated cells) were also detected in vivo in the peripheral blood of patients with active tuberculosis, which reversed after antimycobacterial therapy. M. tuberculosis-infected DCs produced many different cytokines, but not IL-15, and addition of IL-15 to cocultures of infected DCs and Vγ9Vδ2 T cells caused efficient differentiation of these latter with generation of effector memory and terminally differentiated cells, which were capable of reducing the viability of intracellular M. tuberculosis. Overall, this study provides a further piece of information on the complex relationship between important players of innate immunity during mycobacterial infection.

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

“…52,53 Lack of IL-15 production by infected DCs results in the absence of gd T cell effector functions, making the differentiation of central memory gd T cells into effector memory cells difficult. 49 These data could support the implementation of IL-15 expressing DCs into clinical trials. [54][55][56][57] Impact of DCs on effector functions of gd T cells The two main effector functions of gd T cells which would be desirable in the context of cancer immunotherapy are a direct cytotoxicity toward tumor cells and an immunomodulatory function through the secretion of pro-inflammatory cytokines including IFN-g and TNF-a.…”

“…For example, Bacillus Calmette-Guerin (BCG)-and Mycobacterium tuberculosis-infected DCs have been shown to induce proliferation of Vg9d2 T cells with a central memory phenotype, both in autologous and allogeneic settings. 48,49 In contrast, DCs infected with HIV are not able to induce Vg9d2 T cell proliferation, 50 indicating that DC-mediated gd T cell proliferation following infection is dependent on the type of pathogen. In the context of infection-related signals, maturation of DCs with pathogen-associated molecular patterns (PAMPs; e.g.…”

“…44 It should however be pointed out that phosphoantigens do not solely influence DC-mediated gd T cell activation. 48,49 Since phosphoantigens are not responsible for the entire effect, there must be other growth factors, cytokines, or contactdependent factors contributing to this crosstalk. 69 Soluble mediators described to induce gd T cell activation are as follows: IL-12 9,71,72 , IL-15 48 , IL-1b, TNF-a 72 and IFN-a/b.…”

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…In this context, DCs infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) undergo maturation by Vc9/Vd2 T cells, activated either with zoledronate/ phosphoantigens or by the BCG infected DCs themselves [37,46]. Meraviglia et al [47] reported that DCs, partially matured upon infection with Mycobacterium tuberculosis, were able to activate Vc9/Vd2 T cells and become fully matured in return. Lastly, Ni et al [48] described a system whereby DCs infected with Brucella exhibited an inhibition of maturation, but upon co-culture with Vc9/Vd2 T cells underwent full maturation with regard to upregulation of costimulatory molecules.…”

γδ-T cells: an unpolished sword in human anti-infection immunity

“…125 In addition to cellular regulation, the development, proliferation and activation of cd-T cells in anti-infection immune responses are also controlled by multiple soluble molecules, in particular cytokines. Similarly to NK cells, both IL-7 and IL-15 are indispensable during the development and homeostasis of cd-T cells, 126 while IL-15, 127 accompanied by IL-17 and IL-22, has also been found to contribute to the activation and expansion of cd-T cells during M. tuberculosis 53 infection. A similar effect that is mediated by IL-23 has been found in Listeria monocytogenes 128 infection as well.…”