Pre-existing influenza antibodies, younger age, and increased CD4 TE+EM predict influenza vaccination responses in transplant recipients

Human Immunology · 2026-03-10

Recipients of kidney transplants require lifelong immunosuppression therapy which is associated with a reduced response to vaccinations. We conducted a longitudinal study of influenza vaccination in US Veteran kidney transplant recipients and correlated demographic factors and T cell characteristics to the immunological outcome of the vaccination. Our data suggest that a consistent history of annual vaccination during the 3 years prior is linked to an increase in influenza antibodies prior to vaccination. High influenza titers post-vaccination are associated with younger age, increased CD4 T E+EM cells and pre-existing anti-influenza IgG levels but no association of CMV serostatus or immunologically aged T cells was detected. Thus, preexisting IgG antibodies, age, and CD4 T E+EM cells could serve as predictors for the successful influenza vaccination in this at-risk population informing targeted interventions to improve vaccine responses, prevent infections, and reduce influenza-associated comorbidities.

FOXP-stabilization of the <i>Il2ra</i> super-enhancer structure augments Treg fitness

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-17

Abstract Gene expression in regulatory T cells (Tregs) is context-dependent and maintains peripheral immune homeostasis. FOXP3 is lineage defining but not sufficient for Treg function or persistence. To define the cell-intrinsic roles of the FOXP3 paralogs FOXP1 and FOXP4, we generated and studied mice with Treg-specific deletion of Foxp1 and/or Foxp4 . FOXP1 and FOXP4 are required to maintain the peripheral Treg pool through enhancing Il2ra transcription, thereby promoting sustained high-level expression of IL-2Rα and thus of the high-affinity IL-2Rαβγ complex. Integrating RNA-seq and ATAC-seq with previously published ChIA-PET and publicly available data, we propose a model of Il2ra transcriptional regulation in which in which FOXP1 and FOXP4 anchor chromatin looping of the Il2ra locus in mature Tregs, augment super-enhancer activity, and drive sustained CD25 expression. Our results reveal a unique role of FOXP1, and to a lesser extent FOXP4, in controlling Treg homeostasis. One Sentence Summary FOXP1 and FOXP4 regulate chromatin architecture at the Il2ra locus, promoting sustained CD25 expression and maintaining the peripheral Treg pool.

Normal Treg homeostasis and suppressive function require both FOXP1 and FOXP4

JCI Insight · 2025-08-12 · 4 citations

FOXP3+ Treg cells are critical for immune tolerance. Genetic deletion of the Forkhead domain-containing proteins of the FOXP-subfamily member FOXP1 from Tregs results in impaired function associated with reduced CD25 expression and IL-2 signaling, but to date the only other FOXP family member expressed in Tregs, FOXP4, has been minimally studied. To investigate the potential functional interactions among FOXP family members in Tregs, we specifically deleted Foxp1, Foxp4, or both in FOXP3+ committed Tregs in mice. Our findings show that mice with combined, but not individual, deficiency in FOXP1 and FOXP4 exhibit lymphoproliferation, inflammation, autoimmunity, and early lethality. The combined absence of FOXP1 and FOXP4 in Tregs results in an activated/effector-like phenotype with compromised suppressive function in peripheral lymphoid organs, an enhanced germinal center response, and proinflammatory cytokine production. We further show that FOXP1 and FOXP4 bind to Il2ra promoter regions to regulate CD25 expression in Tregs. Through pairwise comparison among mouse strains with Treg-specific deletion of Foxp1, Foxp4, or both, our findings indicate a nonredundant but insufficient role of FOXP4 in Treg function.

Immuno-amnesia: Without B cells, T cells cannot remember

Science Immunology · 2025-06-06

Why B cells are needed for optimal CD8 T cell memory.

Sugar-coated CAR T for sweeter cell therapies

Science Immunology · 2025-12-05

Deletion of the SPPL3 sheddase improves allogeneic CAR T cell persistence.

Spatialomic Analysis of Kidney Biopsies Identifies Differential Abundance of Transcripts and Cell Types by Glomerular and Non-Glomerular Regions Associated with Kidney Allograft Loss

American Journal of Transplantation · 2025-08-01

The Immune Microenvironment of Transplant Glomerulitis

Kidney International Reports · 2025-06-18 · 1 citations

Introduction: Transplant glomerulitis is a morphological lesion seen in kidney allograft rejection that is associated with poor outcomes; however, little is known about how immune cells infiltrate and organize specifically within glomeruli. Methods: We used Co-Detection by Indexing (CODEX) multifluorescent imaging to measure 52 protein markers in a retrospective cohort of 41 human allograft nephrectomies (ANs) and evaluated the immunological landscape of transplant glomerulitis. Results: Characterization of 18 cell types identified diverse immune cells within inflamed glomeruli, with unique phenotypes and compositions compared with the extraglomerular microenvironment. Immunological phenotypes were conserved across glomeruli within individuals and associated with the general state of injury, with M1 macrophages and effector CD8 T cells associated with mild inflammation. Distance-based spatial analysis further revealed a profibrotic community composed of M2 macrophages, memory CD8 T cells and exhausted CD8 T cells surrounding endothelial cell hubs. These interaction networks were associated with regions of adverse glomerular remodeling, expression of profibrotic proteins, and were more prevalent in individuals with C4d-positive rejection. Conclusion: These results implicate distinct cell-cell interactions as hallmarks of alloimmune injury and chronic remodeling during transplant glomerulitis and may give rise to new tools for histological risk assessment of clinical rejection syndromes.

Advancing mouse models for transplantation research

American Journal of Transplantation · 2024-01-13 · 10 citations

CAR-ving away OX40L with engineered T _regs

Science Immunology · 2024-11-01

OX40L–CAR-T regs show promise for treating autoimmunity and transplantation rejection.

Forced Revision Can Still Inform—Lessons and Questions From the “Original” TWO Study

Transplantation · 2024-06-07

Kidney transplantation is the preferred treatment for patients with end-stage kidney disease, but the life-long immunosuppression required remains a source of long-term complications. One approach to minimize or eliminate immunosuppression that has gained traction recently is the use of cellular therapies. The ONE Study, a multicenter phase 1 trial, demonstrated the safety of CD4+Foxp3+ regulatory T cells (Treg) in the setting of kidney transplantation.1 However, the specifics of which cells to use, how to isolate them, and how to administer them are active areas at several international centers. In the accompanying article, Brook et al2 described results from a limited study with lymphodepletion and delayed administration of ex vivo expanded polyclonal Treg. The TWO study (Transplantation Without Overimmunosuppression)3 was originally designed as a phase 2b randomized control trial of delayed administration of autologous Treg therapy in living donor kidney transplant recipients. Study participants underwent induction with alemtuzumab (anti-CD52) lymphodepletion therapy followed by maintenance immunosuppression with mycophenolate mofetil (MMF) and tacrolimus. Participants in the cell therapy arm had progressive MMF reduction starting at 12 wk posttransplant with full discontinuation of MMF at 6 mo at which time they also received 5–10 × 106 Treg/kg; control participants were maintained on both drugs and received no cell therapy. The provided protocol biopsies performed at 38 wk posttransplant showed no acute rejection, and the dose of tacrolimus was reduced from a goal of 5–10 to 4–6 ng/dL in the cell therapy arm. Participants were followed up to 18 mo posttransplant with clinical assessment and immune monitoring performed longitudinally. Unfortunately, the COVID-19 pandemic led authorities in the United Kingdom to suspend the use of alemtuzumab limiting enrollment to a total of only 9 participants, 4 in the cell therapy arm, 3 in the control arm, and 2 were withdrawn due to COVID-19-related delays in transplantation. The TWO study was subsequently substantially modified,3 so these 7 represent a unique cohort with no additional participants. Overall, lymphodepletion followed by delayed administration of CD4+Foxp3+ Treg was well tolerated and there were no safety concerns. All 3 patients were weaned to single-drug immunosuppression with “low-dose” tacrolimus without evidence of acute rejection. However, despite the lower tacrolimus target postinfusion in the cell therapy arm, drug levels were not statistically different from those in control participants. Protocol biopsies performed at 9 mo post-transplant/12 wk post-infusion demonstrated a lack of cellular infiltrate and minimal tubulointerstitial fibrosis. Notably, 1 patient in each group developed mild clinical cytomegalovirus (CMV) disease that was treated with 3 wk of valganciclovir, leading to full resolution; neither group had any participants with evidence of BK virus nephropathy. Immune monitoring studies showed a trend toward an increase in Treg number and frequency, but only during the first 1–2 wk postinfusion. Although there was transient depletion of B cells following alemtuzumab, naive and marginal-zone B-cell numbers were similar between the 2 groups at the time of cell infusion and the 72-wk endpoint of the study. The overall findings of safety and a lack of acute rejection are reassuring. An earlier phase 1 study by the Northwestern group showed that Treg could be safely given 2 mo after alemtuzumab,4 but those patients remained on MMF, whereas the current study with Treg infusion delayed until 6 mo posttransplant suggests that minimization to tacrolimus monotherapy can be achieved using this approach. Similarly, the STEADFAST study (NCT04817774) is a phase 1/2a trial of Chimeric Antigen Receptor (CAR)-Treg with delayed administration at 3 mo following rabbit anti-thymocyte globulin induction.5 Based on data publicly presented but not yet published, this study has had no significant safety concerns at this time. Combined with the current study, there is ever-increasing evidence that autologous Treg can be safely administered after lymphodepletion. Regarding infectious complications, unlike The ONE Study where the cell therapy arm had a noticeable absence of CMV viremia,1 1 of 4 patients in the cell therapy arm had CMV reactivation; similar to the frequency of 1 of 3 control participants. Although not a safety signal and only a small number of participants, these data may decrease the optimism surrounding the correlation between cellular therapy and protection from viral reactivation. From a mechanistic stance, the authors provide data for major T- and B-cell populations including longitudinal Treg frequencies, with no statistical differences between the cell therapy and control groups. Unfortunately, the authors were not able to quantify changes in donor-reactive T cells after the infusion because of technical challenges. With the biopsy tissue obtained as part of the protocol and the group’s growing expertise in spatial profiling, it will be interesting to see high-dimensional data from the tissues. Will there be differences in innate or adaptive cell infiltration or signals that could point toward markers consistent with successful immunosuppression tapering? These types of studies, combined with planned gene expression studies as well as cytokine and metabolic profiling (per the original protocol provided in the Supplement), are sure to provide the community with invaluable mechanistic insights. Overall, the conclusions that can be drawn from this study are limited because of the numbers enrolled; the authors should be acknowledged and applauded for disseminating the data on this unique set of patients as it has the potential to guide the planning of new trials involving lymphodepletion and delayed administration of Treg post–kidney transplantation.