Multifunctional cytokine production reveals functional superiority of memory CD4 T cells

Westerhof, Lotus M.; McGuire, Kris; MacLellan, Lindsay; Flynn, Ashley; Gray, Joseph V.; Thomas, Matthew C.; Goodyear, Carl S.; MacLeod, Megan K. L.

doi:10.1002/eji.201848026

Cited by 29 publications

(38 citation statements)

References 53 publications

(67 reference statements)

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“…As especially those patients in general generate higher frequencies of cytokine co-producers than those in the other two groups with acute and chronic infectious complications, and they can be interpreted as having a better disease-control ( Figure 2 ). This is in line with many studies showing that these multifunctional T-cells are needed to clear infections and are superior to single-producers ( 20 , 33 – 36 ). Indeed, this T-cell profile of higher quality seems to be protective against infectious complications in children with enlarged adenoids ( Figure 2 ).…”

Section: Discussionsupporting

confidence: 87%

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation

et al. 2020

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Every sixth child suffers from hypertrophy of the adenoid, a secondary lymphoid organ, at least once in childhood. Little is known about the impact of pathogen-provocation vs. developmental impact on T-cell responses after 1 year of age. Therefore, developmental and infection-driven influences on the formation of T-cell-compartments and-multifunctionality in adenoids were analyzed taking into account patient's history of age and inflammatory processes. Here, we show that in adenoids of 102 infants and children similar frequencies of naïve, effector, and memory T-cells were accumulated, whereby history of suffering from subsequent infection symptoms resulted in lower frequencies of CD4 + and CD8 + T-cells co-expressing several cytokines. While patients suffering from sole nasal obstruction had balanced Th1-and Th17-compartments, Th1 dominated in patients with concomitant upper airway infections. In addition, analysis of cytokine co-expressing CD4 + and CD8 + T-cells showed that children at the age of three or older differed significantly from those being 1-or 2-years old, implicating a developmental switch in T-cell differentiation at that age. Yet, dissecting age and infectious history of the patients revealed that while CD8 + T-cell differentiation seems to be triggered by development, CD4 + T-cell functionality is partly impaired by infections. However, this functionality recovers by the age of 3 years. Thus, 3 years of age seems to be a critical period in an infant's life to develop robust T-cell compartments of higher quality. These findings identify important areas for future research and distinguish an age period in early childhood when to consider adjusting the choice of treatment of infections.

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Section: Discussionsupporting

confidence: 87%

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation

et al. 2020

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“…We found previously that while CD4 T cell effectors responding to IAV in the spleen and draining lymph nodes produce high levels of IL-2, only about 10% of cells responding in the lung at the peak of the anti-viral response demonstrate robust IL-2 production [10]. This is in stark contrast to the strong IL-2 production potential observed from CD4 T cells that develops in the lungs only after the clearance of virus as well as at memory timepoints [12, 67, 68]. We propose that these findings reflect two distinct kinds of control on IL-2 production by CD4 T cells.…”

Section: Discussionmentioning

confidence: 99%

Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation

et al. 2019

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Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals to reduce CD4 T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 T cells and improves the outcome of IAV infection in vaccinated mice. Finally, we show that IL-2 administration drives rapid and extremely potent lung inflammation involving NK cells, which can synergize with sublethal IAV infection to promote acute death. These results suggest that IL-2 production is not necessarily an indicator of protective CD4 T cells, and that the lung environment is particularly sensitive to IL-2-induced inflammation during viral infection.

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“…A study has shown that with the help of CD4 T cells, CTL polyfunctionality and anti-tumor effect both increased 25 . Moreover, CD4 memory T cells display multifunctional and resistant cytokine production in response to stimulation 26 . A study about bladder cancer also indicated that a high fraction of T cells CD4 memory activated was associated with better outcomes 27 .…”

Section: Discussionmentioning

confidence: 99%

Infiltrating Immune Cells in Gastric Cancer: A Novel Predicting Model for Prognosis

Wang

et al. 2021

J. Cancer

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Multifunctional cytokine production reveals functional superiority of memory CD4 T cells

Cited by 29 publications

References 53 publications

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation

Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation

Infiltrating Immune Cells in Gastric Cancer: A Novel Predicting Model for Prognosis

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