The role of CD8 + T lymphocytes in chronic obstructive pulmonary disease: a systematic review

Objective and design This systematic review aims to establish the role of CD8 + T lymphocytes in COPD. Methods Forty-eight papers published in the last 15 years were identified for inclusion. Results CD8 + T-cells are increased in the lungs of patients with COPD (17 studies, 16 positive) whereas in the circulation, findings were inconclusive. Activation of CD8 + T-cells was enhanced in lungs (four studies, three positive) but cell phenotype was unclear. There was substantial evidence of a higher proportion of type 1 CD8 + (Tc1) cells in COPD (11 studies, 9 positive), though the population of type 2 (Tc2) cells was also increased (5 studies, 4 positive). CD8 + T-cells in COPD exhibited greater expression of cytotoxic proteins (five studies, five positive). Studies assessed a variety of questions so evidence was insufficient to draw firm conclusions. The role of CD8 + T-cells at acute exacerbation of COPD and also their contribution to alveolar destruction can only be hypothesised at this stage. Conclusions Not only is the number of CD8 + T-cells increased in COPD, these cells have increased capacity to exert effector functions and are likely to contribute to disease pathogenesis. Several mechanisms highlighted show promise for future investigation to consolidate current knowledge. Electronic supplementary material The online version of this article (10.1007/s00011-020-01408-z) contains supplementary material, which is available to authorized users.

: Studies investigating extracellular markers and phenotype of CD8+ T lymphocytes in COPD. Eight studies were identified. Four examined expression of activation markers on CD8+ T lymphocytes in COPD, two of which also investigated killer immunoglobulin receptor expression. Cell phenotype was analysed in four studies whilst chemokine receptor expression was examined in two, as was the CD103 integrin. American Thoracic Society guidelines Peripheral blood Peripheral blood: S and COPD-CS had significantly more peripheral blood CD8+ T cells which were activated ex-vivo compared to HNS. There was no significant differences in the activation of CD8+ T cells when comparing COPD-exS, S or COPD-CS. CD8+ T cell activation was positively correlated with the number of cigarettes smoked.
A lower proportion of CD8+ T cells expressed inhibitory killer immunoglobulin receptor (KIR) in COPD-CS and S compared to HNS. There was no difference in expression of activating KIRs between the groups In induced sputum, a significantly higher proportion of CD8+ T cells in COPD-CS and COPD-exS were activated ex vivo compared to HNS. A significantly higher proportion of CD8+ T cells from COPD-CS were activated compared to S. 9 COPD-CS, 7 COPD-exS Peripheral blood: the percentage of naive and memory CD8+ T cells was not significantly different between groups.
In BAL, the percentage of memory CD8+ T cells was greater than in peripheral blood whereas the percentage of naive CD8+ T cells was lower than in peripheral blood BAL COPD patients had a significantly greater number of CD8+ T cells per ml BAL compared to HNS Proportion of CD8+ T cells expressing CCR3 was significantly greater in COPD and S compared with HNS and the same was seen for CCR5. There was no difference in CCR3 and CCR5 between COPD and S.
When data from COPD and S groups was combined, CCR5 expression on CD8+ T cells in BAL of current smokers was significantly higher compared to ex-smokers. There was a positive correlation between BAL CD8+ CCR5 expression and pack year history.
Lung explants -there was a significantly higher level of CCL5 in COPD compared to S. Stimulation with LPS had no effect on chemokine release. CCL11 production in COPD and S was low and similar, and also was not altered by LPS stimulation. Epithelial CD8+ T cells were higher in COPD compared to HNS but no different than S Percentage of CD8+ T cells expressing activating KIR NKG2D was increased in COPD and S compared to HNS. The percentage of activated CD8+ T cells (CD69+) was increased in COPD and S compared to HNS. CD69 fluorescence intensity was also increased in CD8+ T cells from COPD subjects and S compared to HNS. There were no differences in fluorescence intensity in NKG2D or HLA-DR on CD8+ T cells. Peripheral blood Significant decrease in the percentage of CD8+/CD3+ T cells in smokers with COPD compared to HNS and S. There was increased proportion of CD8+/CXCR3+ T cells in COPD-CS compared to S and HNS so this increase is smokingindependent.
The percentage of CD28+/CD8+ T cells as increased in COPD-CS and S compared to HNS. There was decreased chemotactic activity of CD8+ T cells to monocyte chemoattractant protein 1 in COPD-CS and S compared to HNS.
The percentage of cytotoxic effector CD8+ T cells was significantly higher in COPD-CS and S compared to HNS, shows a smoking related increase in cytotoxicity.

Mikko et al [18]
Human 2013 Increased intraepithelia l (CD103+) CD8+ T cells in the airways of smokers with and without chronic obstructive pulmonary disease 27 COPD-CS, 11 COPD-exS, 40 S, 40 HNS GOLD I and II BAL Peripheral blood BAL: Proportion of BAL CD8+ T cells expressing CD103 was significantly higher in COPD-CS and S compared to HNS. COPD-CS also had significantly higher CD103+ CD8+ T cells than COPD-exS. Also, COPD-CS and S had significantly lower proportion of naive CD27+ CD69-T cells in the CD8+ CD103+ population compared to HNS. COPD-exS had higher frequencies of these naive cells than COPD-CS.
Peripheral blood: no difference in CD8+ CD103+ T cells between groups.