4–1BB signal stimulates the activation, expansion, and effector functions of γδ T cells in mice and humans

Abstract

We show here that the expression of 4-1BB is rapidly induced in γδ T cells following antigenic stimulation in both mice and humans, and ligation of the newly acquired 4-1BB with an agonistic anti-4-1BB augments cell division and cytokine production. We further demonstrate that γδ rather than αβ T cells protect mice from Listeria monocytogenes (LM) infection and 4-1BB stimulation enhances the γδ T-cell activities in the acute phase of LM infection. IFN-γ produced from γδ T cells was the major soluble factor regulating LM infection. Vγ1 + T cells were expanded in LM-infected mice and 4-1BB signal triggered an exclusive expansion of Vγ1 + T cells and induced IFN-γ in these Vγ1 + T cells. Similarly, 4-1BB was induced on human γδ T cells and shown to be fully functional. Combination treatment with human γδ T cells and anti-hu4-1BB effectively protected against LM infection in human γδ T cell-transferred NOD-SCID mice. Taken together, these data provide evidence that the 4-1BB signal is an important regulator of γδ T cells and induces robust host defense against LM infection.Keywords: 4-1BB r IFN-γ r Listeria monocytogenes r γδ T cells Introduction 4-1BB (CD137), a member of the TNFR superfamily, is an inducible T-cell costimulatory molecule [1][2][3]. With few exceptions, expression of 4-1BB is activation dependent. In fact, 4-1BB is not detected (<3%) on resting T cells or T-cell lines [4]. However, 4-1BB is stably upregulated when T cells are activated by a variety of agonists such as plate-bound anti-CD3, concanavalin A, phytohemagglutinin, interleukin (IL)-2, IL-4, and CD28, as well as phorbol myristic acetate and ionomycin, either in isolation or in combination with APCs [5,6]. Expression of 4-1BB has been reported on activated CD4 + T cells, CD8 + T cells, NK cells, and NKT cells, and in a constitutive manner on CD11c + dendritic cells (DCs) and CD4 + CD25 + Treg cells [1,3,[7][8][9]. Functional 4-1BB Correspondence: Dr. Byoung S. Kwon e-mail: bskwon@ncc.re.kr expression has also been observed on myeloid cells, including monocytes, neutrophils, mast cells, and eosinophils [10]. Once expressed, 4-1BB binds with a high affinity to 4-1BB ligand (4-1BBL) that is present on a variety of APCs such as DCs, B cells, and macrophages [1,4]. Stimulation of 4-1BB along with TCR engagement was shown to cause T-cell expansion, cytokine induction, and upregulation of anti-apoptotic genes, and to prevent activation-induced cell death [1][2][3]. The available data strongly suggest that 4-1BB is a bonafide CD8 + T-cell-activating molecule, although 4-1BB expression is comparable in CD4 + and CD8 + T cells. The differential effect of 4-1BB on CD4 + and CD8 + T cells is not completely understood [11][12][13].γδ T cells, a distinct lineage of T lymphocytes, represent 0.5-3% of all the T cells in the blood and secondary lymphoid organs [14,15]. γδ T cells constitute the major T lymphocyte population in mucosal tissues, where they play specific roles in the regulation of immune responses to many pathogens [16][17][18][19][20][21][22]...

4-1BB Agonist Focuses CD8+ Tumor-Infiltrating T-Cell Growth into a Distinct Repertoire Capable of Tumor Recognition in Pancreatic Cancer

“…Only cultures that grew in at least one of the two conditions are represented in Figure 3B. Since NK cells and γδ TCR + T cells can also express 4-1BB, we stained for their presence in primary cultures to determine if the a4-1BB antibody being used was stimulating their growth (33,34). Indeed we found that three cultures with a4-1BB were enriched with a CD3 − CD56 + population that was a greater proportion of the culture than CD3 + TIL (Fig.…”

Triple costimulation via CD80, 4-1BB, and CD83 ligand elicits the long-term growth of Vγ9Vδ2 T cells in low levels of IL-2

“…Correia and colleagues [17] reported that phosphoantigens alone were not able to activate gd T cells and that the addition of a high dose of IL-2 was crucial for complete gd T cell activation. Recent studies demonstrated that engagement of a variety of costimulatory molecules, including CD80 and 4-1BBL, also known as CD137L, promotes the proliferation and survival of peripheral Vg9Vd2 T cells [18][19][20]. Moreover, mature DCs, pretreated with aminobisphosphonate, were able to induce the amplification of pure gd T cells that fail to activate in cancer patients [21], suggesting that stimulatory signaling through multiple costimulatory receptors can activate and expand the gd T cells.…”

Role of gamma-delta (γδ) T cells in autoimmunity

“…IL-17A-and IFN-g-producing cells have a protective role in the bacterial infection, in which IL-17 helps in the recruitment of neutrophils, whereas IFN-g helps in the early innate response [58,73]. 4-1BB is another TNFR superfamily molecule expressed on activated gd T cells and stimulates the activation, expansion, and effector function of gd T cells [74]. These studies suggest that TNF superfamily members play an important role in the development and function of gd T cells.…”