CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential
Authors: Jonathan M Levitt
William K Decker
Vanaja Konduri
Jonathan Vazquez-Perez
Damilola Oyewole-Said
Scott A Weldon
Matthew M Halpert
Journal: Frontiers in Immunology (2021)
Discipline: IMMUNOLOGY
Keywords: CD161; KLRB1; T-cell; TH1 polarization; effector memory.
Affiliations: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, United States., Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States., Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States., Scott Department of Urology, Baylor College of Medicine, Houston, TX, United States., Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, United States.

Abstract:  NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4+ and CD8+ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4+ (TH17 MAIT cells) and CD8+ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8+NK1.1+/CD8+CD161+ cells in comparison to CD8+ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8+CD161+ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8+ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered. 

Retracted: No

PubPeer comments:
 ![file] In this review article, Konduri and colleagues provide an overview of the function and role of CD161+CD8+ T cells. The authors claim, that CD161 has two ligands: LLT1 and PILAR. As CD161-LLT1 interaction is well established (Aldemir et al., 2005; Rosen et al., 2005), the interaction between CD161 and PILAR is unclear. It was demonstrated by Huarte and colleagues (Huarte et al., 2008) that CD161 can bind PILAR. However, later it was shown that PILAR interacts with NKp65, but not CD161 (Spreu et al., 2010). Therefore, I believe that the claim by Konduri and colleagues regarding two different ligands of CD161 is false. References: Aldemir et al., 2005. *J Immunol*. Cutting edge: lectin- like transcript 1 is a ligand for the CD161 receptor. Rosen et al., 2005. *J Immunol*. Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. Huarte et al., 2008. *Blood*. PILAR is a novel modulator of human T-cell expansion. Spreu et al., 2010. *Proc. Natl. Acad. Sci. U.S.A.* Interaction of C- type lectin-like receptors NKp65 and KACL facilitates dedicated immune recognition of human keratinocytes. , 
 #1 This is a review article. You know, review of the literature? One paper says one thing, another paper says another thing. We are not the final arbiters of what is absolutely true or absolutely false. A review article simply reports what is in the literature and makes no claim one way or the other regarding veracity - a concept which can sometimes take decades to sort out. There is certainly no scientific consensus here one way or the other. , 
 #2 Thank you, I perfectly understand your point. I just pointed out that, according to the general understanding of CD161 biology, only one ligand of CD161 exists. And yes, I think that there is scientific consensus regarding ligands of CD161. If you want to read more about it, you can find similar arguments in earlier reviews concerning CD161, namely in Fergusson et al., 2011, Kirkham Carlyle, 2014 and Biau0142oszewska Malejczyk, 2018. References: Fergusson et al., 2011. *Front Immunol*. CD161-expressing human T cells. Kirkham Carlyle, 2014. *Front Immunol*. Complexity and diversity of the NKR-P1:Clr (Klrb1:Clec2) recognition systems. Biau0142oszewska Malejczyk, 2018. *Crit Rev Immunol*. Biological and clinical significance of human NKRP1A LLT1 receptor ligand interactions. ,