aGvHD

Could dual targeting of TNFRSF25 and CD25 minimize gastrointestinal graft-versus-host disease?

Innate lymphoid cells (ILCs) and regulatory T cells (Tregs) are both found in abundance in the gastrointestinal (GI) tract and are imperative for the development of immune homeostasis and tolerance.1 Growing evidence highlights the role of Treg and ILC signaling in modulating gut-associated graft-versus-host disease (GvHD).2

Two membrane-bound proteins are associated with the modulatory activity of Tregs and ILCs. Firstly, CD25 is a component of the interleukin 2 (IL-2) receptor and is largely responsible for cellular responses to IL-2 stimulation.3 Secondly, the tumor necrosis factor receptor superfamily member 25 (TNFRSF25) responds to TL1A stimulation, providing co-stimulatory signals in activated lymphocytes while also enhancing expansion and function of Treg cells. Transgenic and knockout mice studies have uncovered the modulatory role of the TNFRSF25-TL1A axis in a number of critical immunological conditions such as ileitis or colitis.4

Sabrina N Copsel, University of Miami, US, and colleagues investigated what impact dual activation of the CD25 and TNFRSF25 pathways has on Treg and ILC populations in the GI tract of healthy mice. The results were recently presented at the 2020 Transplant and Cellular Therapy Meeting, Marriott World Center Orlando, US, and the GvHD Hub hereby presents a summary.1

Study Design

Assessing response of Treg and ILC cells to treatment with TL1A-FP and IL-2

  • Untreated B6-Nur77GFP or B6-Nur77GFPFoxP3RFP mice received one of the following treatments over the course of one week
    • IL-2 (n = 3)
    • TL1A-Ig fusion protein (TL1A-FP) (n = 3)
    • TL1A-FP plus IL-2 (n = 3)
  • Flow cytometry (FC) was used to determine T-cell receptor (TcR) activation of Treg and ILC cells in various GI tissues. Frequency and mean fluorescent intensity (MFI) in Nur77GFP cells were used as parameters for TcR activation

Assessing Treg and ILC2 levels post-total body irradiation (TBI) in pre-TBI FP+IL-2 treated mice

  • BALB/c mice (n = 3) were treated with TL1A-FP + IL-2 24hours prior to receiving 8.5 Gy of TBI
  • FC was used to determine the frequency of Treg and ILC cells in various GI tissues such as the small intestine (SI) and large (LI) of mice, five days following TBI

Results

  • Activation with TL1A-FP and TL1A-FP + IL-2 led to significant expansion of CD4/Treg cells but not CD8 cells in the LI. Only moderate expansion was seen with IL-2 alone
  • The SI and the lamina propria of the LI exhibited a significantly higher frequency of activated Tregs and ILCs (> 45%) compared to other lymphohematopoietic (LHC) compartments such as spleen and cervical lymph nodes
  • BALB/c mice treated with TL1A-FP + IL-2 prior to TBI demonstrated significantly elevated Treg and ILCs in the GI tract for ≥ 1 week following irradiation

Conclusions

  • Activation of Treg and ILC cells by TL1A-FP and IL-2 is dependent on compartmental location, with significantly higher levels obtained in the GI compartments compared to other LHC compartments
  • Selective activation of Treg cells can be achieved with TL1A-FP only, while ILCs require both TL1A-FP and IL-2
  • When pre-treated with both TL1A-FP and IL-2, the Treg and ILC population in the GI tract of TBI treated mice was significantly enhanced for more than one week, suggesting a potential therapeutic strategy for patients undergoing hematopoietic stem cell transplant (HSCT)
  • These preliminary data, alongside existing evidence that the TNFRSF25 and CD25 pathways are implicated in other GI inflammatory disorders, provide scope for further investigation into their regulatory role in GI-GvHD
References
  1. Copsel SN. et al. TNFRSF25 and CD25 Stimulation Expands Tregs and ILC2s in the GI Tract: Recipient Modulation Pre-HSCT. Paper presented at: Transplant and cellular therapy meeting; Feb 2020; Orlando, US. https://www.bbmt.org/article/S1083-8791(19)30990-5/abstract [Accessed March 8, 2020]
  2. Bruce DW. et al. Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease. J Clin Invest. 2017 May 1; 127(5): 1813 –1825. DOI:10.1172/JCI91816
  3. Flynn MJ & Hartley JA. The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer. Br J Haematol. 2017 Oct; 179(1): 20 –35. DOI: 10.1111/bjh.14770
  4. Valatas V. TL1A (TNFSF15) and DR3 (TNFRSF25): A co-stimulatory system of cytokines with diverse functions in gut mucosal immunity. Front Immunol. 2019 Mar 27; 10:583. DOI: 10.3389/fimmu.2019.00583
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