Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis
Abstract
Regulatory T cells (Tregs) are essential to preventing autoimmunity. They depend upon interleukin-2 (IL-2) for optimal function and, due to high expression of the CD25 subunit of the IL-2 receptor, are 10-fold more sensitive to IL-2 than effector T cells (Teffs). Consequently, low-dose IL-2 can be used to expand Tregs preferentially, a therapeutic strategy that has shown promise in a number of autoimmune and inflammatory conditions—including graft-versus-host disease and lupus—where IL-2 driven expansion correlates with improvements in some clinical markers of disease activity.
Autoimmunity is a frequent delayed complication of treatment with the lymphocyte-depleting drug alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Here, using in vitro assays, a pre-clinical mouse model and an experimental medicine study, we investigated whether low-dose IL-2 could selectively expand Tregs in alemtuzumab-treated RRMS patients.
Six months after alemtuzumab treatment, the frequency of patient-derived naïve CD4+ Teffs expressing high-affinity IL-2 receptors increased from 30.11% ± 5.09% to 72.88% ± 5.57%, and the density of receptors per cell increased, rendering them six times more sensitive to IL-2 in vitro, at concentrations that typically favour Tregs. Using a human CD52-expressing transgenic mouse model of alemtuzumab treatment, we found that IL-2 could still preferentially expand Tregs, but only when administered at a later time point, corresponding to more than 6 months post-treatment in patients.
Guided by these findings, we evaluated low-dose IL-2 for Treg expansion in a prospective open-label mechanistic study of RRMS patients who had received alemtuzumab more than 6 months previously. IL-2, at a dose and frequency similar to that previously shown to expand Tregs in autoimmune diabetes (0.3 × 106 IU/m2 twice a week), was well tolerated and safe, but unexpectedly failed to expand Tregs.
We discuss the potential reasons underlying this lack of response, ruling out sIL2RA-related neutralization and instead considering ceiling effects on Treg proliferation, Treg exhaustion and intrinsic Treg dysfunction in MS as possible contributors. Together, our findings demonstrate that low-dose IL-2 alone is not an effective strategy for promoting Treg expansion post-alemtuzumab and is therefore not a viable approach on its own for preventing post-treatment autoimmune complications.
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BibTeX
@article{georgieva2026lowdose,
title = {{Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis}},
author = {Zoya G Georgieva and Sarah K Howlett and Daniel B Rainbow and Valerie Coppard and Lou Ellis and Lorna B Jarvis and Evangelia Williams and Jennie H M Yang and Bo Sun and Timothy Tree and Alasdair J Coles and Linda S Wicker and Joanne L Jones},
journal = {Brain},
year = {2026},
month = may,
doi = {10.1093/brain/awag171},
url = {https://doi.org/10.1093/brain/awag171},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis
AU - Zoya G Georgieva
AU - Sarah K Howlett
AU - Daniel B Rainbow
AU - Valerie Coppard
AU - Lou Ellis
AU - Lorna B Jarvis
AU - Evangelia Williams
AU - Jennie H M Yang
AU - Bo Sun
AU - Timothy Tree
AU - Alasdair J Coles
AU - Linda S Wicker
AU - Joanne L Jones
PY - 2026
DA - 2026/05/13
JO - Brain
DO - 10.1093/brain/awag171
UR - https://doi.org/10.1093/brain/awag171
AB - Regulatory T cells (Tregs) are essential to preventing autoimmunity. They depend upon interleukin-2 (IL-2) for optimal function and, due to high expression of the CD25 subunit of the IL-2 receptor, are 10-fold more sensitive to IL-2 than effector T cells (Teffs). Consequently, low-dose IL-2 can be used to expand Tregs preferentially, a therapeutic strategy that has shown promise in a number of autoimmune and inflammatory conditions—including graft-versus-host disease and lupus—where IL-2 driven expansion correlates with improvements in some clinical markers of disease activity. Autoimmunity is a frequent delayed complication of treatment with the lymphocyte-depleting drug alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Here, using in vitro assays, a pre-clinical mouse model and an experimental medicine study, we investigated whether low-dose IL-2 could selectively expand Tregs in alemtuzumab-treated RRMS patients. Six months after alemtuzumab treatment, the frequency of patient-derived naïve CD4+ Teffs expressing high-affinity IL-2 receptors increased from 30.11% ± 5.09% to 72.88% ± 5.57%, and the density of receptors per cell increased, rendering them six times more sensitive to IL-2 in vitro, at concentrations that typically favour Tregs. Using a human CD52-expressing transgenic mouse model of alemtuzumab treatment, we found that IL-2 could still preferentially expand Tregs, but only when administered at a later time point, corresponding to more than 6 months post-treatment in patients. Guided by these findings, we evaluated low-dose IL-2 for Treg expansion in a prospective open-label mechanistic study of RRMS patients who had received alemtuzumab more than 6 months previously. IL-2, at a dose and frequency similar to that previously shown to expand Tregs in autoimmune diabetes (0.3 × 106 IU/m2 twice a week), was well tolerated and safe, but unexpectedly failed to expand Tregs. We discuss the potential reasons underlying this lack of response, ruling out sIL2RA-related neutralization and instead considering ceiling effects on Treg proliferation, Treg exhaustion and intrinsic Treg dysfunction in MS as possible contributors. Together, our findings demonstrate that low-dose IL-2 alone is not an effective strategy for promoting Treg expansion post-alemtuzumab and is therefore not a viable approach on its own for preventing post-treatment autoimmune complications.
SN - 0006-8950
SN - 1460-2156
ER -