Treating γδT cells as Individuals May Help Develop New Cancer Treatments

γδ T cells are a subset of T cells that bridge innate and adaptive immunity. γδ T cells bind and recognize a broad range of foreign materials with their “γδ” receptors. These foreign entities can include proteins and lipids from pathogens as well as host stress molecules. This is the innate part of their function; it is fairly non-specific. They then generate either CTL-like (toxic) or Th-like (helper) responses against these pesky materials. This is the adaptive part of their function; it is more specific (1). Often, it is thought that all γδ T cells behave similarly, in the way that was just described.

A growing body of evidence, however, including a recent paper by Yin et. al. (2), suggests that different subsets of γδ T cells perform unique functions (3). In their work, Yin and coworkers found that one type of γδ T cell, Vg1 γδ T cells, inhibits the antitumor response of another type of γδ T cell, Vγ4 γδ T cells. (Vγ1 and Vγ4 refer to a particular gene segment that codes for part of the receptor chain; think of it as a receptor flavor).

In a previous study (4), Yin and coworkers found that Vγ4 γδ T cells killed tumors using INFγ (a signaling molecule that can: tell other cells to kill the tumor, prevent blood and nutrient flow to the tumor, and prevent spreading of the tumor by constructing a barrier around it (1)) and perforin (a molecule that kills a tumor by poking holes in it (1)). In this study, Yin et al. found that Vγ1 γδ T cells inhibit the anti-tumor response of Vγ4 γδ T by using signaling molecule IL-4.

Yin and co-workers placed Vγ1 γδ T cells , Vγ4 γδ T cells, and tumor cells in mice in different combinations and monitored tumor growth. Vγ4 γδ T cells alone suppressed the tumor. Addition of Vγ1 γδ T cells reduced this suppression. They obtained similar results when they performed the experiments in vitro (outside of mice, in culture).

When they separated the two types of cells by a membrane in vitro, they observed the same loss of tumor suppressor function. This suggests that the Vγ1 γδ T cells do not depend on direct cell-to-cell contact to inhibit Vγ4 γδ T cells and instead depend on a soluble mediator. This conclusion was further confirmed by a dye staining experiment that showed that the two types of cells localized to different parts of the tumor and were therefore unlikely to directly contact each other at all.

The soluble mediator molecule was determined to be IL-4. Suppressing IL-4 restored Vγ4 γδ T tumor suppression abilities. Furthermore, adding IL-4 alone, but not Vγ1 γδ T cells, to Vγ4 γδ T cells suppressed antitumor properties. The relationship between the two cell types came full circle when Yin and coworkers found that IL-4 down regulates NKG2D (Natural Killer Group 2 receptor, common to NK cells and γδ T cells), a receptor that tells Vγ4 γδ T cells to make IFNγ and perforin. IL-4 interferes with IFNγ and perforin. Thus, molecules made by Vγ1 γδ T cells interfere with molecules made by Vγ4 γδ T cells.

The study leaves some questions unanswered. For example, why do the different γδ T cell subsets localize to different parts of the tumor? How does IL-4 down regulate NKG2D receptors? More broadly, how do Vγ4 γδ T and Vγ1 γδ T cells interact with other cell types? But it also provides novel and potentially useful results. It suggests that Vγ1 γδ T is a regulatory T cell of sorts in that it dampens the response of another type of T cell, Vγ4 γδ T. The study also opens the door for a possible tumor therapy where Vγ1 γδ T cells are selectively killed or inactivated so that Vγ4 γδ T cells can be allowed to carryout out their tumor-killing mission.

Reference:

Yin, Z. et. al. 2011. Regulatory Role of Vγ1 γδ T cells in Tumor Immunity through IL-4 Production. J. Immunol. 187: 4979-4986.

Additional Citations:

(1) Mak, Tak and Mary Saunders. Primer to the Immune Response. California: Elsevier, 2011. Print.

(2) Yin, Z. et. al. 2011. Regulatory Role of Vγ1 γδ T cells in Tumor Immunity through IL-4 Production. J. Immunol. 187: 4979-4986.

(3) Born,W. K., Z. Yin, Y. S. Hahn, D. Sun, and R. L. O’Brien. 2010. Analysis of γδ T cell Functions in the Mouse. J. Immunol. 184: 4055–4061.

(4) He, W. , J. Hao, S. Dong, Y. Gao, J. Tao, H. Chi, R. Flavell, R. L. O’Brien, W. K. Born, J. Craft, et al. 2010. Naturally Activated Vγ4 γδ T cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin. J. Immunol. 185: 126–133.