PRMT5 Associates With the FOXP3 Homomer and When Disabled Enhances Targeted p185erbB2/neu Tumor Immunotherapy

Abstract

Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.

PRMT5 Is Required for T Cell Survival and Proliferation by Maintaining Cytokine Signaling

“…We previously reported that the deletion of PRMT5 in Treg cells leads to their defective peripheral maintenance and function, causing a lethal scurfy-like phenotype in Foxp3 Creyfp PRMT5 fl/fl mice within 4 wk of age. We found that PRMT5 symmetrically di-methylates Foxp3 at arginine 51 and that a point mutation of arginine 51 to lysine on Foxp3 leads to defective Treg function (11). However, taking our current results into consideration, the defective maintenance, activation, and proliferation of PRMT5-deficient Foxp3 + Treg cells may also be attributed to impaired γc signaling.…”

“…This led to the development of PRMT5 inhibitors for cancer therapy and some are under clinical trials (24). We previously demonstrated that PRMT5 inhibition by DS-437 enhances anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in a drug-resistant syngeneic murine breast cancer model by inhibiting Treg function and induction of tumor immunity (11). However, our current study revealed that PRMT5 is also important for conventional T cell responses.…”

“…Recombination-activating gene 2 (RAG2) KO mice were purchased from Taconic Biosciences. CD4 Cre PRMT5 fl/fl mice (B6 background) were described previously (11). CD4 Cre mice and PRMT5 fl/fl mice were used as control for CD4 Cre PRMT5 fl/fl mice.…”

“…Hematopoietic-specific deletion of PRMT5 results in fatal bone marrow aplasia, indicating that PRMT5 is essential for hematopoiesis (9,10). We recently reported on the role of PRMT5 in regulatory T (Treg) cells using Treg-specific PRMT5 conditional knockout mice (11). These mice showed defective Treg maintenance and function in the periphery, which led to a lethal scurfy-like autoimmunity phenotype.…”

FoxP3 in Treg cell biology: a molecular and structural perspective

“…Conditional knock‐out of the PRMT5 gene in T regs causes severe Scurfy‐like autoimmunity. Consistently, pharmacological ablation of PRMT5 activity by DS‐437 also reduces human T reg functions, which enhance the anti‐tumor effects of anti‐erbB2/ neu monoclonal antibody‐targeted therapy in mice bearing CT26 human epidermal growth factor receptor (HER2) tumors .…”