Human Lung Tissue-Resident Memory T Cells Are Re-Programmed but Not Eradicated with Systemic Glucocorticoids After Acute Cellular Rejection
Introduction
Lung transplantation remains one of the most important therapeutic interventions for patients with end-stage pulmonary diseases, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, and pulmonary arterial hypertension. Despite major advances in surgical techniques, immunosuppressive regimens, and post-operative monitoring, acute cellular rejection (ACR) continues to represent a major complication after transplantation. ACR is driven primarily by alloimmune responses mediated by T lymphocytes that recognize donor antigens and initiate inflammatory damage within the transplanted lung. Among the immune cell populations involved in this process, tissue-resident memory T cells (TRM cells) have emerged as particularly significant.
TRM cells are a specialized subset of memory T lymphocytes that permanently reside within tissues rather than circulating through blood and lymphoid organs. In the lung, TRM cells provide rapid and localized immune protection against respiratory pathogens. However, the same biological properties that make these cells effective defenders against infection may also contribute to transplant rejection and chronic inflammatory injury. Their persistence within the graft, resistance to depletion, and rapid effector functions make them uniquely important in transplant immunology.
Systemic glucocorticoids remain the standard first-line therapy for acute cellular rejection after lung transplantation. Drugs such as methylprednisolone and prednisone are widely used because of their potent anti-inflammatory and immunosuppressive effects. Traditionally, glucocorticoids were thought to suppress immune activation broadly and eliminate pathogenic immune responses. Yet recent immunological research has demonstrated that lung TRM cells are not fully eradicated following steroid treatment. Instead, these cells undergo transcriptional, metabolic, and functional re-programming while surviving within the transplanted tissue.
The concept that TRM cells are re-programmed rather than eliminated has important implications for understanding persistent inflammation, recurrent rejection, chronic lung allograft dysfunction (CLAD), and long-term transplant survival. This essay explores the biology of human lung TRM cells, their role in acute cellular rejection, the mechanisms of glucocorticoid action, and the evidence supporting the persistence and re-programming of these cells after treatment. The discussion further examines the clinical implications of these findings and future therapeutic strategies targeting TRM biology in lung transplantation.
Tissue-Resident Memory T Cells: Biological Characteristics
Definition and Discovery of TRM Cells
Tissue-resident memory T cells are a distinct population of antigen-experienced T cells that permanently reside within non-lymphoid tissues. Unlike central memory T cells (TCM) and effector memory T cells (TEM), which circulate between blood and lymphoid organs, TRM cells establish long-term residency within tissues such as the skin, intestine, brain, and lung.
The discovery of TRM cells transformed the understanding of adaptive immunity. Earlier immunological models assumed that immunological memory depended primarily on circulating lymphocytes. However, studies in mucosal tissues demonstrated that certain memory T cells remain fixed in tissues after infection and provide rapid local responses upon re-exposure to pathogens.
Lung TRM cells are particularly abundant due to constant environmental exposure to airborne antigens, viruses, bacteria, and pollutants. These cells are strategically positioned within airway epithelium and interstitial lung tissue, allowing immediate responses to respiratory infections.
Phenotypic Markers of Lung TRM Cells
Human lung TRM cells express characteristic surface markers associated with tissue retention and survival. Common markers include:
CD69
CD103
CD49a
CXCR6
PD-1 n CD69 suppresses sphingosine-1-phosphate receptor signaling, preventing tissue egress. CD103 interacts with E-cadherin on epithelial cells, anchoring TRM cells within tissues. These markers help distinguish TRM populations from circulating T cells.
TRM cells also display unique transcriptional programs involving transcription factors such as:
Hobit
Blimp-1
Runx3
Notch signaling pathways
These transcriptional regulators reinforce tissue residency, survival, and effector function.
Functional Properties
Lung TRM cells possess several functions relevant to transplantation:
- Rapid cytokine production
- Cytotoxic activity
- Local immune amplification
- Recruitment of additional immune cells
- Long-term tissue persistence
Upon antigen recognition, TRM cells rapidly produce inflammatory cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-17 (IL-17). These cytokines recruit monocytes, neutrophils, dendritic cells, and circulating lymphocytes.
Although beneficial during infection, excessive activation of these pathways contributes to alloimmune injury during transplantation.
Acute Cellular Rejection in Lung Transplantation
Pathophysiology of Acute Cellular Rejection
Acute cellular rejection is characterized by immune-mediated injury directed against donor lung tissue. It occurs when recipient T cells recognize donor alloantigens presented through direct or indirect antigen presentation pathways.
Histologically, ACR is defined by perivascular and interstitial lymphocytic infiltration. Severe cases may involve airway inflammation, endothelial damage, and epithelial injury.
The immune cascade of ACR involves:
Activation of donor-reactive T cells
Cytokine release
Recruitment of inflammatory leukocytes
Tissue destruction
Amplification of adaptive immune responses
Repeated episodes of ACR are associated with worse long-term outcomes and increased risk of chronic lung allograft dysfunction.
Role of TRM Cells in Rejection
Traditionally, transplant rejection was attributed mainly to circulating alloreactive T cells. However, recent evidence indicates that donor-derived and recipient-derived TRM cells contribute substantially to rejection.
Lung TRM cells are uniquely positioned to respond rapidly because they already reside within the graft tissue. Their local presence allows them to:
Detect donor antigens quickly
Produce inflammatory mediators immediately
Sustain local immune activation
Resist systemic immunosuppressive depletion
Recipient-derived TRM cells may infiltrate and establish residency within the graft over time, while donor-derived TRM cells may persist temporarily after transplantation.
Studies using bronchoalveolar lavage, lung biopsies, and single-cell RNA sequencing have demonstrated that activated TRM populations expand during episodes of acute rejection.
Cytokine Environment During ACR
The inflammatory environment of ACR strongly supports TRM activation. Elevated cytokines include:
IFN-γ
IL-2
IL-15
TNF-α
IL-17
CXCL9 and CXCL10 chemokines
IL-15 is particularly important because it promotes TRM survival and maintenance. This cytokine-rich environment may explain why TRM cells persist despite immunosuppressive therapy.
Glucocorticoids in Lung Transplantation
Mechanisms of Action
Glucocorticoids exert broad immunosuppressive effects through genomic and non-genomic pathways. After entering cells, glucocorticoids bind cytoplasmic glucocorticoid receptors (GRs), which then translocate into the nucleus.
The glucocorticoid receptor complex influences gene expression through:
Transactivation of anti-inflammatory genes
Transrepression of pro-inflammatory genes
Interaction with transcription factors such as NF-κB and AP-1
These mechanisms reduce inflammatory cytokine production and suppress immune cell activation.
Effects on T Cells
Glucocorticoids affect multiple aspects of T-cell biology:
Reduced cytokine synthesis
Inhibition of proliferation
Induction of apoptosis
Altered migration patterns
Metabolic suppression
Activated circulating T cells are particularly sensitive to glucocorticoid-induced apoptosis. However, tissue-resident populations may exhibit greater resistance.
Clinical Use in Acute Cellular Rejection
High-dose intravenous methylprednisolone is commonly administered during episodes of ACR. Treatment often includes:
Intravenous pulse steroids
Oral prednisone taper
Additional immunosuppressive adjustments
Clinical improvement is frequently observed after therapy, including reduced inflammation and improved pulmonary function. Nevertheless, recurrent rejection remains common.
This clinical paradox suggested that pathogenic immune populations might survive treatment despite apparent short-term suppression.
Re-Programming Rather Than Eradication of TRM Cells
Emerging Evidence from Human Studies
Modern techniques such as single-cell transcriptomics, flow cytometry, spatial transcriptomics, and T-cell receptor sequencing have provided detailed insights into TRM biology after glucocorticoid treatment.
These studies reveal that lung TRM cells frequently survive systemic glucocorticoid therapy. Rather than disappearing, they undergo significant phenotypic and transcriptional changes.
Researchers have observed:
Persistence of TRM populations after treatment
Reduced inflammatory cytokine production
Altered metabolic activity
Modified transcriptional profiles
Temporary functional suppression
This phenomenon is described as “re-programming” rather than eradication.
Transcriptional Re-Programming
Glucocorticoid exposure changes gene expression patterns within TRM cells. Key alterations include:
Downregulation of Pro-inflammatory Genes
Genes associated with effector functions become suppressed, including:
IFNG
TNF
GZMB
IL17A
This reduces immediate inflammatory activity.
Upregulation of Survival Genes
At the same time, TRM cells increase expression of genes promoting survival and stress adaptation, such as:
BCL2
FKBP5
anti-apoptotic signaling molecules
These adaptations help the cells withstand steroid exposure.
Persistence of Residency Programs
Importantly, genes associated with tissue residency often remain active. TRM cells continue expressing markers related to tissue retention and survival.
Therefore, glucocorticoids may suppress inflammatory functions without disrupting the core residency identity of TRM cells.
Mechanisms Underlying Steroid Resistance in TRM Cells
Tissue Microenvironment Protection
The lung tissue environment provides protective signals that enhance TRM survival. Cytokines such as IL-15 and TGF-β support tissue residency and resistance to apoptosis.
Cell-to-cell interactions with epithelial cells, fibroblasts, and antigen-presenting cells further reinforce TRM persistence.
Metabolic Adaptation
TRM cells possess unique metabolic programs that may contribute to steroid resistance.
Unlike rapidly proliferating effector T cells, TRM cells rely heavily on:
Fatty acid uptake
Oxidative phosphorylation
Long-term energy conservation
This metabolically quiescent state may reduce susceptibility to glucocorticoid-induced apoptosis.
Additionally, TRM cells express lipid transport proteins that support survival within nutrient-variable tissue environments.
Epigenetic Stability
TRM identity is reinforced through epigenetic modifications, including:
Histone acetylation
DNA methylation patterns
Chromatin accessibility changes
These epigenetic programs stabilize residency-associated transcriptional states. Even after glucocorticoid exposure suppresses inflammatory activity, the underlying epigenetic architecture may preserve the capacity for future reactivation.
Differential Glucocorticoid Receptor Signaling
Not all T cells respond identically to glucocorticoids. Variations in glucocorticoid receptor expression, co-regulators, and downstream signaling pathways may influence sensitivity.
TRM cells may express molecular programs that buffer against excessive glucocorticoid-induced apoptosis while still permitting partial functional suppression.
Functional Consequences of TRM Re-Programming
Temporary Suppression Versus Permanent Elimination
One of the most important implications of TRM re-programming is that immunosuppression may be transient rather than definitive.
After steroid therapy:
Cytokine production decreases
Inflammatory activity subsides
Clinical symptoms improve
However, surviving TRM cells retain the capacity for reactivation under appropriate inflammatory conditions.
This may explain recurrent rejection episodes observed in many transplant recipients.
Contribution to Chronic Lung Allograft Dysfunction
Chronic lung allograft dysfunction represents the leading cause of long-term mortality after lung transplantation. Persistent low-grade immune activation contributes to progressive airway fibrosis and loss of graft function.
Re-programmed TRM cells may participate in this chronic process by:
Maintaining inflammatory memory
Producing intermittent cytokine bursts
Recruiting additional immune cells
Sustaining local immune surveillance
Even subclinical activation may gradually damage airway structures.
Balancing Protection and Pathology
Complete elimination of TRM cells could impair protective immunity against respiratory pathogens. Lung transplant recipients already face increased infection risks due to immunosuppression.
Therefore, TRM persistence may have dual consequences:
Beneficial Effects
Protection against viral infections
Rapid local immune responses
Mucosal defense maintenance
Harmful Effects
Persistent alloimmune memory
Recurrent rejection
Chronic inflammation
Fibrotic remodeling
Therapeutic strategies must therefore balance immune suppression with preservation of host defense.
Experimental Techniques Revealing TRM Persistence
Single-Cell RNA Sequencing
Single-cell RNA sequencing (scRNA-seq) has revolutionized transplant immunology. This technique allows researchers to characterize individual immune cells at transcriptomic resolution.
Studies using scRNA-seq have shown that TRM populations persist after steroid therapy but exhibit altered transcriptional states.
Researchers can identify:
Distinct TRM subsets
Activation signatures
Steroid-response pathways
Clonal expansion patterns
T-Cell Receptor Sequencing
T-cell receptor (TCR) sequencing tracks clonally expanded T-cell populations.
Persistent donor-reactive TRM clones have been identified before and after glucocorticoid treatment, demonstrating that many pathogenic clones survive therapy.
This finding strongly supports the concept of functional modulation rather than cellular elimination.
Spatial Transcriptomics
Spatial transcriptomics provides information about gene expression within tissue architecture.
This method reveals that TRM cells remain localized near:
Airways
Vascular structures
Sites of prior inflammation
Spatial persistence reinforces their potential role in recurrent tissue injury.
Multiparameter Flow Cytometry
Flow cytometric analyses confirm persistence of CD69+ and CD103+ T-cell populations following steroid treatment.
Functional assays show decreased cytokine production immediately after therapy but incomplete loss of effector potential.
Clinical Implications
Limitations of Current Immunosuppressive Strategies
The persistence of TRM cells highlights important limitations of conventional immunosuppressive therapy.
Standard treatments were designed primarily to suppress circulating immune responses. Tissue-resident immune populations may require different therapeutic approaches.
Current glucocorticoid regimens may:
Reduce acute inflammation
Improve short-term graft function
Fail to eliminate pathogenic memory populations
This limitation may contribute to recurrent rejection and chronic graft dysfunction.
Biomarker Development
Understanding TRM biology may improve diagnostic monitoring.
Potential biomarkers include:
TRM-associated transcriptional signatures
Cytokine profiles
TCR clonality patterns
Bronchoalveolar lavage immune phenotyping
These biomarkers could help identify patients at high risk for recurrent rejection.
Personalized Immunosuppression
Future transplant management may involve individualized immunological profiling.
Patients with persistent inflammatory TRM signatures could receive targeted therapies beyond conventional steroids.
Precision immunology approaches may optimize:
Drug selection
Treatment intensity
Duration of therapy
Infection risk management
Future Therapeutic Strategies
Targeting TRM Survival Pathways
Novel therapies may directly interfere with TRM maintenance signals.
Potential targets include:
IL-15 signaling
TGF-β pathways
CXCR6-mediated retention
Metabolic pathways
Blocking these survival mechanisms could reduce pathogenic TRM persistence.
Epigenetic Therapies
Because TRM identity is epigenetically stabilized, epigenetic therapies may alter long-term residency programs.
Potential interventions include:
Histone deacetylase inhibitors
DNA methylation modifiers
Chromatin remodeling agents
These therapies remain experimental but may reshape pathogenic immune memory.
Cellular Therapies
Regulatory T-cell therapies represent another promising strategy.
Regulatory T cells (Tregs) may suppress pathogenic TRM responses while preserving protective immunity.
Adoptive Treg transfer and engineered immune tolerance strategies are currently under investigation.
Localized Immunotherapy
Localized delivery of immunosuppressive agents directly into the lung could provide stronger suppression of tissue-resident immune populations while minimizing systemic toxicity.
Inhaled immunomodulators may become increasingly important in lung transplantation.
Ethical and Clinical Challenges
Risk of Infection
Aggressive targeting of lung TRM cells could compromise pulmonary immune defense.
TRM cells play crucial roles in protection against:
Influenza
Respiratory syncytial virus
SARS-CoV-2
Bacterial pneumonias
Transplant recipients already face elevated infectious risks, making excessive immune depletion potentially dangerous.
Balancing Immune Tolerance and Surveillance
The ideal transplant immune state involves tolerance toward donor tissue while maintaining pathogen defense.
Achieving this balance remains one of the greatest challenges in transplantation medicine.
The persistence of TRM cells illustrates the complexity of selectively suppressing harmful immune responses without abolishing beneficial immunity.
Long-Term Monitoring
Persistent TRM populations may require lifelong monitoring.
Emerging molecular diagnostics could allow earlier detection of:
Re-activation states
Inflammatory transitions
Fibrotic progression
Improved surveillance may reduce irreversible graft damage.
Broader Implications for Immunology
The discovery that TRM cells are re-programmed rather than eradicated extends beyond transplantation.
Similar principles may apply in:
Autoimmune diseases
Chronic inflammatory lung diseases
Viral persistence
Cancer immunotherapy
Vaccine responses
Understanding tissue-resident immunity is transforming modern immunology by emphasizing local immune ecosystems rather than solely systemic immune responses.
The lung serves as a particularly important model because of its continuous environmental exposure and delicate balance between defense and tolerance.
Conclusion
Human lung tissue-resident memory T cells represent a highly specialized and resilient immune population that plays a central role in lung transplantation immunology. During acute cellular rejection, TRM cells contribute to localized inflammatory injury through rapid cytokine production, cytotoxic activity, and amplification of alloimmune responses.
Systemic glucocorticoids remain effective first-line therapies for acute rejection because they suppress inflammatory gene expression and reduce immune activation. However, growing evidence demonstrates that these therapies do not fully eliminate pathogenic lung TRM cells. Instead, TRM cells undergo extensive transcriptional, metabolic, and functional re-programming while retaining core features of tissue residency and survival.
This persistence has profound implications for recurrent rejection, chronic lung allograft dysfunction, and long-term transplant outcomes. The concept of immune re-programming rather than eradication challenges traditional views of immunosuppression and highlights the need for new therapeutic strategies specifically targeting tissue-resident immune populations.
Future advances in single-cell biology, precision immunology, and targeted therapeutics may enable more effective control of pathogenic TRM cells while preserving essential protective immunity. Achieving this balance will be critical for improving long-term graft survival and patient outcomes after lung transplantation.
Ultimately, the study of lung TRM cells reveals the remarkable adaptability of the human immune system and underscores the importance of tissue-specific immunity in health, disease, and transplantation medicine.
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