In a recent review published in Nature Reviews Immunology, researchers elucidated the mechanisms of long-term T lymphocyte lodgement in tissues other than lymphoid tissues and the reasons for the transient residency of specific subsets of tissue-resident memory T (T_RM) lymphocytes.

Background

T_RM lymphocytes reside in tissues for varying durations, after which they return to circulation. Studies have documented archetypical T_RM lymphocytes with intrinsic properties for long-term residence in several tissues other than lymphoid tissues, except the lungs. Memory T lymphocytes induced by respiratory infections are preserved in circulation; however, pulmonary T_RM lymphocyte counts decline with a concomitant reduction in T lymphocyte-mediated immune protection.

About the review

In the present review, researchers highlighted the atypical phenomenon demonstrated by memory-type T lymphocytes of pulmonary tissue egress. They speculated on the implications of the phenomenon, particularly during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Archetypical type of T_RM lymphocytes and mechanisms in T_RM lymphocyte egress from tissues

Based on transplantation mismatch experiments, antibody assessments, and antibody labeling infusion in vivo, mice T_RM lymphocytes remain after the depletion of circulating T lymphocytes from tissues and comprise the cluster of differentiation 103+ (CD103⁺) CD8+ T lymphocytes. The CD103+ T_RM lymphocytes showed high enrichment in skin epithelium, female reproductive tract, and small intestine. At epithelial sites, the interactions between CD103 and its ligand, i.e., E-cadherin, probably play a vital role in cellular adhesion and subsequent retention.

In addition, CD103-expressing CD8⁺ T_RM lymphocytes are present in brain tissues but not in the secondary lymphoid organs. CD103⁺ CD8⁺ T lymphocytes have been identified truly as T_RM lymphocytes. The expression of tissue exit-associated genes, such as the C-C chemokine receptor type 7 (CCR7) gene, and genes coding for sphingosine-1-phosphate receptors 1 and 5, are lowered in T_RM lymphocytes. On the contrary, key upregulated genes include T-bet (T-box expressed in T cells), EOMES (eomesodermin), BLIMP1 (B lymphocyte-induced maturation protein-1), and HOBIT.

Notably, HOBIT and BLIMP1 are involved in natural killer cell and natural killer T lymphocyte development, which confer innate immune protection and permanently reside in mice tissues. RUNX3 (runt-related transcription factor 3) contributed to T_RM lymphocyte formation by indirectly or directly regulating KLF2 (krüppel-like factor 2) and BLIMP1 expression and regulating retention components.

RUNX3 is critically involved in CD8⁺ T lymphocyte formation and function. Transforming growth factor-beta (TGF-β) is also involved in T_RM lymphocyte formation and existence by facilitating tissue entry via selectin upregulation and can regulate several transcription regulators and cytokine-driven survival factors during CD8⁺ T_RM lymphocyte development. The mechanisms that enable the permanent lodgement of CD103-expressing CD8⁺ lymphocytes among non-lymphoid tissues involve RUNX3-mediated transcriptional networks downstream of TGF-β receptor signaling.

RUNX3-mediated transcription is lacking among CD4⁺ T_RM lymphocytes, which utilize extrinsic chemokine-based and cellular accumulation networks for retention in tissues, and in CD103⁻ T_RM lymphocytes due to lower TGF-β expression. CD8⁺ T_RM lymphocyte counts show an intrinsic decline in the lung and liver, and the egress is based on an in-situ antigen stimulation via peptide challenge.  

T_RM lymphocyte exit from pulmonary tissues and immune protection against SARS-CoV-2

Mice CD103⁺ CD8⁺ tissue T cells fit the TRM cell description since they engage in TGFβ–RUNX3 residency programs. However, CD103⁺ CD8⁺ pulmonary T_RM lymphocytes are exceptions, not requiring stimulation by local antigens for dislodgement. In addition, the tissue-exiting memory T lymphocytes retain cellular surface CD103 expression, indicating that lymph nodes draining pulmonary tissues are distinctive since they have a substantive memory-type CD8⁺ T lymphocyte subset.

Pulmonary CD103-expressing CD8⁺ T_RM lymphocytes are mature and express T^RM lymphocyte-associated transcription factors such as NR4A1 (nuclear receptor 4A1), HOBIT, BHLHE40 (basic helix-loop-helix family member E40), and aryl hydrocarbon receptor (AhR).

Pulmonary inflammation results in CD8⁺ and CD4⁺ T lymphocyte recruitment for combating invading pathogenic organisms. The cells include TEM (effector memory T) lymphocytes that recirculate continuously between tissues other than those of lymphoid type and the bloodstream. After the infection resolves, most T lymphocytes recruited exit or are dead. As a result, local immunological surveillance is left to TEM lymphocytes and potent T_RM lymphocytes. With time, a few T_RM lymphocyte subsets vanish, and the resident cell population shows high enrichment of CD103⁺ CD8⁺ T_RM lymphocytes that confer durable local-level immune protection against reinfections.

In pulmonary tissues, CD103-expressing CD8⁺ T_RM lymphocytes are lost gradually after the resolution of infection, and the cells agglomerate in the proximal lymph nodes exiting from the CD103⁺ CD8⁺ T_RM– deficient lower respiratory tract tissues. Thus, the lungs are prone to reinfections. The loss of T_RM lymphocytes is critical to limit ongoing damage to the delicate oxygen-exchange lung architecture. Lung T_RM cell residency is unstable and transient, resulting in surveillance dependent on recirculating populations, with a concomitant decline in local T cell immunity.

Hybrid immunity from COVID-19 vaccination and SARS-CoV-2 infection has steadily declined, which may be due to the numerical decay of anti-SARS-CoV-2 TRM cells, similar to that of CD103⁺ CD8⁺ T_RM lymphocytes in mice. T_RM lymphocytes have an innate immune alarm, and the innate response has been reported as a key mediator of coronavirus disease 2019 (COVID-19)-related pulmonary pathology.

Conclusion

Overall, the study findings highlighted the TRM lymphocyte transcription, mechanisms involved in archetypical T_RM lymphocyte egress from pulmonary tissues, and their implications regarding respiratory infections such as COVID-19.