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Interleukin-7 Driven Lymphocyte Proliferation Enhances T-cell Recruitment to Regenerating Peripheral Nerve after Injury
Michael J Finnan, MS1; Lauren Schellhardt, BS2; Snyder-Warwick K Alison, MD3; Mackinnon E. Susan, MD4; Matthew D Wood, PhD2
1Washington University School of Medicine, St. Louis, MO; 2Washington University School of Medicine, St Louis, MO; 3Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO; 4Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO

Background: T-cells are beneficial in promoting regeneration in many tissue types, including muscle and peripheral nerve. We have previously shown that T-cells function in nerve regeneration by recruiting eosinophils, stimulating IL-4 secretion, and polarizing macrophages towards a pro-regenerative M2 phenotype. Administration of exogenous IL-7 has been shown to induce T-cell proliferation in sepsis, but has not been explored as a possible approach to improve T-cell functions during tissue regeneration. Here, we sought to understand whether exogenous IL-7 can be used in the context of nerve injury to augment regeneration.
Method: The sciatic nerve of BALB/c mice were transected and a 3 mm nerve gap injury was repaired with an empty conduit for a standardized gap-repair model. Beginning on the day of surgery, mice were given intraperitoneal injections of 1.5 ug IL-7 + 7.5 ug M25 stabilizing antibody or sham injections of saline every other day. On day 21, peripheral blood and the regenerated nerve tissue were harvested for analysis by flow cytometry and immunohistochemistry respectively.
Results: Compared to control, the IL-7 group had higher proportions of circulating T-cells (49% vs 38% of all lymphocytes,P<0.0001), and a higher ratio of CD4+ to CD8+ T-cells (4.0 vs 3.3,P<0.001). Among cells in the regenerating nerve gap, T-cells were more than twice as common in the IL-7 group when compared to control (4.3% vs 1.6% CD3+,P<0.0001). Both the percentage of total macrophages (14% vs 9% CD68+,P<0.05) and M2 polarized macrophages (85% vs 65% CD206+/CD68+,P<0.01) were higher in the IL-7 group. Eosinophil quantity was not different for the IL-7 group compared to controls (2.4% vs 1.6% SiglecF+,P=0.11). Both groups demonstrated qualitative evidence of axon regeneration and Schwann cell repopulation as evidence by B3-tubulin and S100 staining respectively.
Conclusions: Exogenous IL-7 is a novel, well-tolerated therapeutic agent that augments T-cell recruitment and the immune microenvironment in the setting of nerve injury. Greater T-cell density within the nascent nerve tissue was associated with a more exaggerated pro-regenerative phenotype, which may enable faster and more robust recovery after injury. Further experiments to determine what changes in gene expression, motor vs sensory axonal regeneration, and functional recovery this intervention may have are underway; however, IL-7 is a promising new therapeutic target that may enhance endogenous repair mechanisms and further improve surgical outcomes.
Figure 1: IL-7 Treated Mice Demonstrate Enhanced T-cell Recruitment to Regenerating Nerve
Figure 2: Higher T-cell Density is Associated with Greater Macrophages Constituency and Exaggerated M2 Polarization


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