Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment

Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes. CD49b+ Treg cells, which display superior functionality revealed by in vitro and in vivo assays, appear to develop after multiple rounds of cell division and TCR-dependent activation. Accordingly, single-cell RNA-seq analysis placed these cells at the apex of the Treg developmental trajectory. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.

Download Full-text

Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF

Immunity ◽

10.1016/j.immuni.2019.12.002 ◽

2020 ◽

Vol 52 (2) ◽

pp. 295-312.e11 ◽

Cited By ~ 17

Author(s):

Michael Delacher ◽

Charles D. Imbusch ◽

Agnes Hotz-Wagenblatt ◽

Jan-Philipp Mallm ◽

Katharina Bauer ◽

...

Keyword(s):

Transcription Factor ◽

Treg Cells ◽

Lymphoid Organs ◽

Nonlymphoid Tissue ◽

Secondary Lymphoid Organs

Download Full-text

692 Tim-3 expression drives phenotypic and functional changes in Treg in secondary lymphoid organs and the tumor microenvironment, effecting tumor burden

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.692 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A720-A720

Author(s):

Hridesh Banerjee ◽

Hector Nieves-Rosado ◽

Benjamin Murter ◽

Lawrence Kane

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Mouse Model ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Tumor Burden ◽

Lymphoid Organs ◽

Functional Changes ◽

The Impact

BackgroundRegulatory T cells (T reg) are critical mediators of self-tolerance but can also limit effective anti-tumor immunity. We and others previously reported that 40–60% percent of T reg-infiltrating head and neck cancer (HNC) and other tumors highly express Tim-3, compared with about 5% in lymphoid organs, it therefore gets imperative to characterize if Tim-3 is driving any T reg specific function in tumor microenvironment and under homeostasis.MethodsUsing a conditional TIM-3 inducible and knockout mouse model developed in our lab, we have performed syngeneic tumor challenges in T reg-specific Tim-3 transgenic and knockout mice (FoxP3ERT2CreSFS-Tim-3 and FoxP3ERT2Cre-FLEX4). We have also characterized the tumor immune infiltrate of these mice to understand the impact of T reg specific Tim-3induction and deficiency on the immune landscape.ResultsTim-3 induction on T reg leads to rapid growth associated with higher progression of CD8 compartment towards exhaustion, while TIm-3 knockout in T reg specific manner leads top overall decline in T reg compartment in tumors associated with lower exhaustion in the CD8 compartment and decrease in tumor burden,ConclusionsTumor-infiltrating Tim-3+ Treg have enhanced suppressive function and display a more effector-like phenotype. Using a novel mouse model with cell type-specific Tim-3 expression, we show here that expression of Tim-3 by Treg is sufficient to drive Treg to a more effector-like phenotype, and increases suppressive activity, effector T cell exhaustion and tumor growth. We also show that inducible deletion of Tim-3 specifically from Treg enhances anti-tumor immunity and decrease in tumor burden along with a decrease in tumor associated Treg compartment. These findings may help to reconcile previous reports that some Tim-3 antibodies enhance T cell responses in vivo, while expression of Tim-3 has a cell-intrinsic ability to enhance TCR signaling and T cell activation. A major role of Tim-3 was found to be mediated through IL-10 and IL-10 R pathway in both Treg and CD8 compartment. Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of Treg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of Treg in this manner.AcknowledgementsWe acknoledge Dr. Robert L. Ferris and Dr. Greg M. Delgoffe for their inputs and guidance with human and metabolism associated experiments.

Download Full-text