Evidence map›Paper›PMID 34440725›Full record

ReviewCells2021

Implications of a 'Third Signal' in NK Cells.

Mohamed Khalil, Dandan Wang, Elaheh Hashemi, Scott S Terhune, Subramaniam Malarkannan

Open access · goldAbstract readReview
In one paragraph

Review in Cells, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
0.7field-weighted citation impact, top 34% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 13 citations in OpenAlex.

  1. Review
  2. Article
  3. [Research progress of the ULBP-NKG2D axis in autoimmune diseases].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026
    Review
  4. Review
  5. Review
  6. Article
  7. Article
  8. Review
  9. Article
  10. Review
  11. Article
  12. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 1 institution in 1 country.

Mohamed KhalilLaboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.ORCID 0000-0002-6841-9620
Dandan WangLaboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.
Elaheh HashemiLaboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.
Scott S TerhuneDepartment of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Subramaniam MalarkannanLaboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.ORCID 0000-0002-7511-2731
Medical College of Wisconsin · US

Funding

Medical Scientist Training ProgramT32GM080202 · NIGMS · MEDICAL COLLEGE OF WISCONSIN · PI BARBIERI, JOSEPH T, SALZMAN, NITA H · 2010 to 2024
$5.7M
Molecular signature of inflammationR01CA179363 · NCI · MEDICAL COLLEGE OF WISCONSIN · PI MALARKANNAN, SUBRAMANIAM · 2014 to 2018
$1.6M
Molecular mechanisms of signaling co-ordination in innate lymphocytesR01AI102893 · NIAID · MEDICAL COLLEGE OF WISCONSIN · PI MALARKANNAN, SUBRAMANIAM · 2013 to 2016
$1.5M
NCI NIH HHS R01 CA179363NIGMS NIH HHS T32 GM080202NIH HHS R01 AI102893
6 · The paper itself

Abstract

Innate and adaptive immune systems are evolutionarily divergent. Primary signaling in T and B cells depends on somatically rearranged clonotypic receptors. In contrast, NK cells use germline-encoded non-clonotypic receptors such as NCRs, NKG2D, and Ly49H. Proliferation and effector functions of T and B cells are dictated by unique peptide epitopes presented on MHC or soluble humoral antigens. However, in NK cells, the primary signals are mediated by self or viral proteins. Secondary signaling mediated by various cytokines is involved in metabolic reprogramming, proliferation, terminal maturation, or memory formation in both innate and adaptive lymphocytes. The family of common gamma (γc) cytokine receptors, including IL-2Rα/β/γ, IL-7Rα/γ, IL-15Rα/β/γ, and IL-21Rα/γ are the prime examples of these secondary signals. A distinct set of cytokine receptors mediate a 'third' set of signaling. These include IL-12Rβ1/β2, IL-18Rα/β, IL-23R, IL-27R (WSX-1/gp130), IL-35R (IL-12Rβ2/gp130), and IL-39R (IL-23Rα/gp130) that can prime, activate, and mediate effector functions in lymphocytes. The existence of the 'third' signal is known in both innate and adaptive lymphocytes. However, the necessity, context, and functional relevance of this 'third signal' in NK cells are elusive. Here, we define the current paradigm of the 'third' signal in NK cells and enumerate its clinical implications.

Indexed as

Adaptive ImmunityImmunity, InnateLymphocyte ActivationAnimalsCytokinesHumansKiller Cells, NaturalPhenotypeReceptors, CytokineSignal TransductionCytokinesReceptors, CytokineIFN-γ—interferon gammaIL—interleukinMHC—major histocompatibility complexNatural Killer cellsNCR—Natural killer cell receptorNK cells

Identifiers

PMID34440725
PMCPMC8393955
OpenAlexW3191518865

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.