Abstract
FoxP3+ T cells populate tumors and regulate anti-tumor immunity. The requirement for optimal population of FoxP3+ regulatory T cells in tumors remains unclear. We investigated the migration requirement and stability of tumor-associated FoxP3+ T cells. We found that only memory, but not naïve, FoxP3+ T cells are highly enriched in tumors. Almost all of the tumor-infiltrating FoxP3+ T cells express Helios, an antigen associated either with thymus-generated FoxP3+ T cells or activated T cells in the periphery. The tumor-infiltrating FoxP3+ T cells largely lack CD62L and CCR7, two trafficking receptors required for T cell migration into secondary lymphoid tissues. Instead, the tumor infiltrating FoxP3+ T cells highly express memory/tumor-associated CCR8 and CXCR4. Antigen priming is required for induction of this trafficking receptor phenotype in FoxP3+ T cells and only antigen primed, but not antigen-inexperienced naive, FoxP3+ T cells can efficiently migrate into tumors. While the migration of FoxP3+ T cells into tumors was a readily detectable event, generation of induced FoxP3+ T cells within tumors was unexpectedly inefficient. Genetic marking of current and ex-FoxP3+ T cells revealed that tumor-infiltrating FoxP3+ T cells are highly stable and do not readily convert back to FoxP3− T cells. Taken together, our results indicate that population of tumors with thymus-generated FoxP3+ T cells requires an antigen priming-dependent trafficking receptor switch in lymphoid tissues.
Highlights
FoxP3+ regulatory T cells (Tregs) play critical roles in inducing tolerance in the body [1,2,3,4,5,6]
Tumors are enriched with Helios+ FoxP3+ T cells Helios is known to be preferentially expressed by thymusderived FoxP3+ T cells and activated T cells in proliferation [35,36]
To gain insights into the phenotype of FoxP3+ T cells populating tumors, we examined the expression of Helios in FoxP3+ T cells infiltrating tumors formed in mice
Summary
FoxP3+ regulatory T cells (Tregs) play critical roles in inducing tolerance in the body [1,2,3,4,5,6]. Naıve FoxP3+ T cells are generated in the thymus and programmed to migrate mainly to secondary lymphoid tissues [7]. Some memory FoxP3+ T cells migrate into various non-lymphoid tissues, whereas others preferentially migrate into secondary lymphoid tissues [7]. For these types of tumors, FoxP3+ T cells could affect tumorigenesis by decreasing inflammation. FoxP3+ T cells are frequently found in human tumors, and their presence within some types of tumors predicts reduced patient survival [16,17,18]. The number of FoxP3+ T cells positively correlated with the patient survival rate [19,20,21,22]
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