CD4+/CD8+ ratio

The CD4+/CD8+ ratio is the ratio of T helper cells (with the surface marker CD4) to cytotoxic T cells (with the surface marker CD8). Both CD4+ and CD8+ T cells contain several subsets.[1]

The CD4+/CD8+ ratio in the peripheral blood of healthy adults and mice is about 2:1, and an altered ratio can indicate diseases relating to immunodeficiency or autoimmunity.[2] An inverted CD4+/CD8+ ratio (namely, less than 1/1) indicates an impaired immune system.[3][4][5] Conversely, an increased CD4+/CD8+ ratio corresponds to increased immune function.[6]

Obesity and dysregulated lipid metabolism in the liver leads to loss of CD4+, but not CD8+ cells, contributing to the induction of liver cancer.[7] Regulatory CD4+ cells decline with expanding visceral fat, whereas CD8+ T-cells increase.[8]

Decreased ratio with infection

A reduced CD4+/CD8+ ratio is associated with reduced resistance to infection.[9]

Patients with tuberculosis show a reduced CD4+/CD8+ ratio.[9]

HIV infection leads to low levels of CD4+ T cells (lowering the CD4+/CD8+ ratio) through a number of mechanisms, including killing of infected CD4+. Acquired immunodeficiency syndrome (AIDS) is (by one definition) a CD4+ T cell count below 200 cells per µL. HIV progresses with declining numbers of CD4+ and expanding number of CD8+ cells (especially CD8+ memory cells), resulting in high morbidity and mortality.[10] When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.[3][4][5] Declining CD4+/CD8+ ratio has been found to be a prognostic marker of HIV disease progression.[11]

COVID-19

In COVID-19 B cell, natural killer cell, and total lymphocyte counts decline, but both CD4+ and CD8+ cells decline to a far greater extent.[12] Low CD4+ predicted greater likelihood of intensive care unit admission, and CD4+ cell count was the only parameter that predicted length of time for viral RNA clearance.[12]

Decreased ratio with aging

A declining CD4+/CD8+ ratio is associated with ageing, and is an indicator of immunosenescence.[5][13] Compared to CD4+ T-cells, CD8+ T-cells show a greater increase in adipose tissue in obesity and aging, thereby reducing the CD4+/CD8+ ratio.[13] Amplication of numbers of CD8+ cells are required for adipose tissue inflammation and macrophage infiltration, whereas numbers of CD4+ cells are reduced under those conditions.[14][15] Antibodies against CD8+ T-cells reduces inflammation associated with diet-induced obesity, indicating that CD8+ T-cells are an important cause of the inflammation.[15] CD8+ cell recruitment of macrophages into adipose tissue can initiate a vicious cycle of further recruitment of both cell types.[15]

Elderly persons commonly have a CD4+/CD8+ ratio less than one.[11] A study of Swedish elderly found that a CD4+/CD8+ ratio less than one was associated with short-term likelihood of death.[11]

Immunological aging is characterized by low proportions of naive CD8+ cells and high numbers of memory CD8+ cells,[5][16] particularly when cytomegalovirus is present.[5] Exercise can reduce or reverse this effect, when not done at extreme intensity and duration.[5]

Both effector helper T cells (Th1 and Th2) and regulatory T cells (Treg) cells have a CD4 surface marker, such that although total CD4+ T cells decrease with age, the relative percent of CD4+ T cells increases.[17] The increase in Treg with age results in suppressed immune response to infection, vaccination, and cancer, without suppressing the chronic inflammation associated with aging.[17]

See also

References
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  2. Owen, Judith; Punt, Jenni; Stranford, Sharon (2013). Kuby Immunology. New York: W. H. Freeman and Company. p. 40.
  3. McBride JA, Striker R (2017). "Imbalance in the game of T cells: What can the CD4/CD8 T-cell ratio tell us about HIV and health?". PLOS Pathogens. 13 (11): e1006624. doi:10.1371/journal.ppat.1006624. PMC 5667733. PMID 29095912.
  4. Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, Ligotti ME, Zareian N, Accardi G (2019). "Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention". Frontiers in Immunology. 10: 2247. doi:10.3389/fimmu.2019.02247. PMC 6773825. PMID 31608061.
  5. Turner JE (2016). "Is immunosenescence influenced by our lifetime "dose" of exercise?". Biogerontology. 17 (3): 581–602. doi:10.1007/s10522-016-9642-z. PMC 4889625. PMID 27023222.
  6. Bradshaw PC, Seeds WA, Curtis WM (2020). "COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm". Oxidative Medicine and Cellular Longevity. 2020: 6401341. doi:10.1155/2020/6401341. PMC 7519203. PMID 33014275.
  7. Tran NL, Sitia G (2016). "New players in non-alcoholic fatty liver disease induced carcinogenesis: lipid dysregulation impairs liver immune surveillance". Hepatobiliary Surgery and Nutrition. 5 (6): 511–514. doi:10.21037/hbsn.2016.11.08. PMC 5218901. PMID 28124011.
  8. Krüger K, Eder K, Ringseis R (2014). "Immune and Inflammatory Signaling Pathways in Exercise and Obesity". Am J Lifestyle Med. 10 (4): 268–279. doi:10.1177/1559827614552986. PMC 6125063. PMID 30202282.
  9. Yin Y, Qin J, Dai Y, Zeng F, Pei H, Wang J (2015). "The CD4+/CD8+ Ratio in Pulmonary Tuberculosis: Systematic and Meta-Analysis Article". Iranian Journal of Public Health. 44 (2): 185–193. PMC 4401876. PMID 25905052.
  10. Kumar, Vinay (2012). Robbins Basic Pathology (9th ed.). p. 147. ISBN 9781455737871.
  11. Bruno G, Saracino A, Monno L, Angarano G (2017). "The Revival of an "Old" Marker: CD4/CD8 Ratio". AIDS Reviews. 19 (2): 81–88. PMID 28182620.
  12. Huang W, Berube J, McNamara M, Saksena S, O'Gorman M (2020). "Lymphocyte Subset Counts in COVID-19 Patients: A Meta-Analysis". Cytometry Part A. 97 (8): 772–776. doi:10.1002/cyto.a.24172. PMC 7323417. PMID 32542842.
  13. Kalathookunnel Antony A, Lian Z, Wu H (2018). "T Cells in Adipose Tissue in Aging". Frontiers in Immunology. 9: 2945. doi:10.3389/fimmu.2018.02945. PMC 6299975. PMID 30619305.
  14. Catalán V, Gómez-Ambrosi J, Rodríguez A, Frühbeck G (2013). "Adipose tissue immunity and cancer". Frontiers in Physiology. 4: 275. doi:10.3389/fphys.2013.00275. PMC 3788329. PMID 24106481.
  15. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R (2009). "CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity". Nature Medicine. 15 (8): 914–920. doi:10.1038/nm.1964. PMID 19633658. S2CID 5222216.
  16. Tibbs TN, Lopez LR, Arthur JC (2019). "The influence of the microbiota on immune development, chronic inflammation, and cancer in the context of aging". Microbial Cell. 6 (8): 324–334. doi:10.15698/mic2019.08.685. PMC 6685047. PMID 31403049.
  17. Jagger A, Shimojima Y, Goronzy JJ, Weyand CM (2014). "Regulatory T cells and the immune aging process: a mini-review". Gerontology. 60 (2): 130–137. doi:10.1159/000355303. PMC 4878402. PMID 24296590.
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