Łukasz Wyrożemski1,2
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Shuo- Wang Qiao1,2,3This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2021 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology 1K.G. Jebsen Coeliac Disease Research
Centre, University of Oslo, Oslo, Norway
2Department of Immunology, University of Oslo, Oslo, Norway
3Department of Immunology, Oslo University Hospital, Oslo, Norway Correspondence
Łukasz Wyrożemski and Shuo- Wang Qiao, K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway.
Emails: l.a.wyrozemski@medisin.uio.no;
s.w.qiao@medisin.uio.no Funding information
Stiftelsen Kristian Gerhard Jebsen, Grant/
Award Number: SKGJ- MED- 017
Abstract
Human C- type lectin- like CD161 is a type- II transmembrane protein expressed on the surface of various lymphocytes across innate and adaptive immune systems.
CD161+ T cells displayed enhanced ability to produce cytokines and were shown to be enriched in the gut. Independently of function, CD161 was used as marker of innate- like T cells and marker of IL- 17- producing cells. The function of CD161 is still not fully understood. In T cells, CD161 was proposed to act as co- signalling receptor that influence T- cell receptor- dependent responses. However, conflicting studies were published demonstrating lack of agreement over the role of CD161 dur-ing T- cell activation. In this review, we outline phenotypical and functional conse-quences of CD161 expression in T cells. We provide critical discussion over the most pressing issues including in depth evaluation of the literature concerning CD161 pu-tative co- signalling properties.
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WYROŻEMSKI AND QIAOeffector memory cells (Temra).17 CD161+CD8+ T cells were Tem or Temra cells with minor proportion of Tcm cells, whereas CD161++CD8+ T cells were almost entirely Tem cells.10,15,18 Although linked to memory phenotype, CD161 is not acquired as a result of immune stimulation and both CD161+ T cells as well as CD161- T cells failed to upregu-late surface CD161 upon activation.18,19
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CD161+ T CELLS AREPOTENT CYTOKINE PRODUCERS
Initial studies showed that CD161+CD4+ T cells and CD161+CD8+ T cells produced more cytokines than their
CD161- counterparts. However, this was explained by ob-servation that CD161- T cells encompassed substantial num-ber of naïve T cells that are known to secrete lower cytokine levels than memory T cells.10 It was later demonstrated that memory CD161+CD4+ T cells, both conventional T cells (Tconv) and regulatory T cells (Treg), produced more IFN- γ and IL- 17 than their CD161- memory counterparts.20 Likewise, memory CD161+CD8+ T cells produced signifi-cantly more IFN- γ and IL- 2 than memory CD161- CD8+ T cells.15 In addition, CD161+CD4+ T cells demonstrated pol-yfunctional cytokine production as many of them produced three or more cytokines while CD161- CD4+ T cells pro-duced two or less cytokines.21 Collectively, the differences in cytokine production between CD161+ T cells and CD161- T
FIGURE 1 A, CD161 distribution among circulating CD4+ and CD8+ T cells. One CD161+ and two CD161+ populations exist in CD4+
and CD8+ T cells, respectively. Flow cytometric staining represents analyses of CD161 expression in T cells isolated from peripheral blood of healthy individual. B, Schematic representation of CD161 function in NK cells and T cells. In NK cells, CD161 operates as an inhibitory receptor.
In T cells, CD161 was shown to act as either co- inhibitory receptor or co- stimulatory receptor, or displayed no co- signalling properties at all.
CD161 operates only with simultaneous engagement of the TCR. CD161 does not provide co- signalling in TCR- independent manner nor together with TCR- independent stimulation through IL- 12 + IL- 18. Abbreviations: MHC, Major histocompatibility complex; pMHC, peptide- MHC complex
co-stimulation APC
target cell
T cell NK cell LLT1
LLT1 pMHC
LLT1 MHC
LLT1 MHC
CD161
CD161
CD161 CD161 TCR
TCR
TCR CD8
CD4
CD161
A B
IL-12R
IL-18R
IL-12
IL-18
inhibition
co-inhibition no effect
no effect
no effect
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cells cannot be merely ascribed to memory phenotype, but might be related to the acquisition of CD161.17
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CD161+ T CELLS IN GUTCD161- expressing T cells are enriched in the gut where they might play an important role in the local immunity by participating in the defence against pathogens or encounter-ing dietary antigens.15,22 The majority of CD4+ T cells in the lamina propria as well as CD8+ T cells in the epithe-lium were positive for CD161.23,24 Both CD161+CD4+ T cells and CD161+CD8+ T cells displayed tissue- resident memory phenotype.23,24 In addition, CD161+CD4+ T cells were polyfunctional cytokine producers skewed towards Th1 or Th17 profile.12,24 The reasons behind the preferen-tial accumulation of CD161+ T cells in the intestine are not completely understood. Gut environment may favour differ-entiation and expansion of T cells expressing particular sur-face receptors.25 Alternatively, CD161 could be specifically upregulated by factors present in gut environment such as retinoic acid.20,26 Apart from the presence of CD161+ T cells in the gut, a number of studies demonstrated that CD161 was preferentially expressed on circulating T cells that exhibited gut- homing properties like expression of chemokine receptor 9 (CCR9) or integrin α4β7.20,27 In fact, CD161 was proposed to be involved in lymphocyte transendothelial migration and thereby could facilitate trafficking of CD161- expressing T cells to the intestine. Suggested CD161- mediated transen-dothelial migration might be based on CD161 encountering its ligand on endothelial cells during the early steps of cell adhesion, presumably strengthening lymphocyte- endothelial cell interaction.28 This observation, however, requires further investigation.
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CD161 AS MARKER OF INNATE- LIKE T CELLSCD161- expressing T lymphocytes of different lineages were shown to be related by innate- like response to IL- 12 + IL- 18 in T- cell receptor (TCR)- independent manner.20,29 CD4+, CD8+ and TCRγδ+ T cells marked by CD161 secreted IFN- γ in response to IL- 12 + IL- 18 stimulation that was function-ally uncoupled from CD161.29,30 However, in each case the cytokine production was restricted to CD161++ T cells which, unlike in CD8+ T cells, form relatively minor subsets within CD4+ T cells and TCRγδ+ T cells. In addition, high expression of CD161 was positively correlated with expres-sion of IL- 18R, and thus CD161 coupled with IL- 18R might be used to denote innate- like T cells across different line-ages.29 On the other hand, it was reported that IL- 18R alone might serve as much better marker of innate- like CD4+ T
cells. IL- 18R+CD4+ T cells, but not IL- 18R- CD4+ T cells, responded to cytokine stimulation despite that both subsets contained substantial number of cells positive for CD161.31 To date, only a handful of studies reported innate- like prop-erties of CD161+ T cells, particularly CD161+CD4+ T cells. For example, CD161+ Tconv and CD161+ Treg dis-played innate- like properties as they secreted significantly more IFN- γ than CD161- counterparts when stimulated with IL- 12 + IL- 18.20 Moreover, CD161+CD4+ T cells that ex-pressed promyelocytic leukaemia zinc finger (PLZF) tran-scription factor and were isolated from foetal small intestine produced IFN- γ in response to IL- 12 + IL- 18 stimulation.30 However, the cytokine requirement that is necessary for TCR- independent activation of CD161+CD4+ T cells is not fully understood. CD161+CD4+ T cells secreted IFN- γ in response IL- 12 + IL- 18 stimulation that was further poten-tiated by ligation of death receptor 3 (DR3) with anti- DR3 monoclonal antibodies (mAbs).32 Likewise, tumour necrosis factor- like cytokine 1A (TL1A), a ligand for DR3, enhanced secretion of various pro- inflammatory cytokines from IL- 12 + IL- 18- stimulated CD161+CD4+ T cells.33 Conversely, in one study CD161+CD4+ T cells failed to produce IFN- γ in response to IL- 12 + IL- 18 stimulation. Further addition of either TL1A, IL- 15 or the combined TL1A and IL- 15 was required to achieve IFN- γ secretion from IL- 12 + IL- 18- stimulated cells. Interestingly, innate- like activity was not restricted to CD161+CD4+ T cells as CD161- CD4+ T cells also secreted IFN- γ in reaction to identical TCR- independent stimuli.31 Lastly, innate- like properties designated by CD161 were proposed to be extended beyond T lymphocytes.
CD161+ NK cells produced IFN- γ in response to IL- 12 + IL- 18 stimulation. However, minor subset of CD161- NK cells also secreted IFN- γ in reaction to cytokine stimulation only to lesser extent than CD161+ NK cells. Closer inspection revealed that expression of IL- 18R, although positively correlated with expression of CD161, was high in majority of NK cells regardless the presence of CD161.2 Taken to-gether, even though some studies postulated to utilize CD161 as a marker of innate- like T cells, it is nonetheless unclear whether CD161 expression alone is sufficient to correctly de-note this specific subset of T cells.
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CD161 AS A MARKER OF IL- 17- PRODUCING T CELLSCD161 is widely recognized as a marker of the Th17 lineage.
Cells harbouring Th17- related signatures were present among circulating and gut- resident CD161+CD4+ T cells.12,34 Moreover, both circulating and gut- resident CD161+CD4+
T cells, but not CD161- CD4+ T cells, were the major source of IL- 17 after in vitro stimulation.12,34 However, CD161 alone might be insufficient to precisely mark Th17 cells. Closer
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WYROŻEMSKI AND QIAOexamination revealed that production of IL- 17 was restricted to CD161+CD4+ T cells that were positive for chemokine receptor 6 (CCR6). In contrast, CD161+CCR6- CD4+ T cells did not secrete IL- 17, suggesting that Th17 cells could be more accurately denoted by CD161 coupled with CCR6.11 In addition, Th17 cells exhibited high expression of dipep-tidylpeptidase IV (CD26) and the combination of CD161 or CCR6 combined with CD26 may be utilized to mark Th17 cells.35 On the contrary, it was proposed that co- expression of CD161 and CD39 might better identify a population that is highly enriched in Th17 cells. CD161+CD39+CD4+ T cells secreted IL- 17, displayed classical Th17- related traits such as CCR6 or IL- 23R and could be utilized to monitor Th17 responsiveness during disease such as Crohn's disease.36 In one report, expression of natural killer group 2 member D (NKG2D) molecule defined Th17 subset more specifically than CD161 in patients with Crohn's disease. There, the ma-jority of IL- 17- positive CD4+ T cells expressed both CD161 and NKG2D while IL- 17- negative CD4+ T cells expressed CD161 but not NKG2D.37 CD161 was also recognized as marker of all IL- 17- producing T cells across different T- cell lineages.13 In concordance, CD161 was found on a subset of Treg cells that retained suppressive abilities despite the se-cretion of IL- 17.19,26,38 Furthermore, a minor subset of IL- 17- secreting CD161++CD8+ T cells, designated as Tc17 cells, was found. However, CD161+CD8+ T cells did not produce IL- 17,14 further indicating that CD161 alone might not be a pertinent marker defining T cells capable to produce IL- 17.
In conclusion, although CD161 is increasingly recognized as a marker of IL- 17 producing T cells, particularly Th17 cells, care should be taken when categorising T cells into IL- 17- related phenotype on the basis of CD161 alone.
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CD161 AS CO- SIGNALLING RECEPTORCD161 is generally considered as an inhibitory receptor in NK cells (Figure 1B). CD161 ligation by anti- CD161 mAbs reduced NK cytotoxicity against target cells.1 Similarly, NK cells exposed to LLT1- expressing target cells showed re-duced cytotoxicity3- 5,7,8 and reduced IFN- γ production.3,5,7 In contrast, CD161 is widely regarded as co- signalling re-ceptor in T cells (Figure 1B). Various studies demonstrated that ligation of CD161 by anti- CD161 mAbs or LLT1 influ-enced TCR- dependent T- cell responses.3,39- 41 Neither CD161 ligation alone3,29,39- 41 nor together with TCR- independent stimulation through IL- 12 + IL- 1829,30 was sufficient to in-duce cellular response. Nonetheless, CD161 co- signalling potential in T cells is debated. Ligation of CD161 acted in context- specific manner to either increase3,26,29,39- 42 or de-crease5,30,43,44 TCR- dependent responses or had no effect on cellular responses at all.1,5,30,43,45 It is worth mentioning
that recent study by Mathewson and colleagues showed that CD161 acted as co- inhibitory receptor and prevented killing glioma cells by CD8+ T cells. Disruption of CD161- LLT1 interaction by blocking anti- CD161 mAbs resulted in en-hanced T- cell- mediated cytotoxicity against tumour cells.44 The experimental results considering co- signalling proper-ties of CD161 were summarized in detail in Table 1. The inconsistencies in functional outcomes of CD161 ligation might be partially attributed to different types of experimen-tal protocols, as well as various clones of anti- CD161 mAbs.
Altogether, more research is needed to thoroughly examine the role of CD161 in the context of co- signalling in T cells.
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CONCLUSIONSCD161 is expressed on a substantial fraction of circulating memory T cells, large proportion of gut- resident memory T cells and the great majority of NK cells, acting as inhibi-tory receptor in the latter population. Unlike in NK cells, the role of CD161 in T cells is unclear. It was proposed to act as co- signalling receptor, but various contradicting reports were published illustrating the disagreement over its func-tion during T- cell activafunc-tion. Independently of its putative co- signalling properties, CD161 is agreed to mark IL- 17- producing T cells of different lineages, as well as innate- like T cells that are capable of TCR- independent, cytokine- driven activation. The dual functionality of CD161 as a phenotypic or functional marker reveals the difficulty in exclusively cat-egorising T cells based on the assessment of purely one sur-face receptor. It is possible that CD161 could serve as marker of IL- 17- producing T cells, preferentially in combination with other surface molecules such as CCR6, CD26, CD39 or NKG2D. Similarly, CD161 might be capable to denote innate- like T cells when coupled with additional surface re-ceptors, for example, IL- 18R. More research is necessary to examine these questions.
Ligation of CD161 is capable of triggering diverse re-sponses in T cells and, in some cases, has opposing func-tional impact on NK cells and T cells. However, it remains unclear how CD161 exerts such various functions. CD161 is identical in both cell types.3 Its cytoplasmic domain either lacks any of the known signalling motifs3 or contains non- canonical ITIM motif characterized by diminished inhibitory potential.5 Moreover, it was reported that CD161 can inter-act with Src family kinases,46 but others demonstrated lack of such association.39 Therefore, it is interesting to speculate that, in order to initiate a signalling cascade, CD161 would have to associate with an adaptor molecule in the manner similar to other surface receptors characterized by relatively short cytoplasmic domain lacking clear signalling motifs.47 Furthermore, differential expression of adaptor proteins among T cells, as well as between T cells and NK cells might
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TABLE 1 Summary of experimental results in the published literature regarding CD161 co- signalling properties
Cell type CD161 ligation Results Reference
[T cells] [anti- CD161 (- )] [no effect on proliferation] 1
immature thymocytes from <4 y old
donors anti- CD161 (191B8) increased proliferation 42
NK T- cell clones plate- bound anti- CD161 (191B8) increased proliferation 39
unbound anti- CD161 (191B8) no effect on proliferation
plate- bound anti- CD161 (191B8) increased IFN- γ and IL- 4 production [plate- bound anti- CD161 (DX1)] [increased IFN- γ and IL- 4 production]
T cells anti- CD161 (191B8) increased IFN- γ production 3
P815- LLT1 cells increased IFN- γ production [CD161+ T- cell clones] [anti- CD161 (191B8)] [increased IFN- γ production]
CD161+ T- cell lines plate- bound anti- CD161 (DX1) increased IFN- γ production
increased proliferation 40
[CD161+ T cells] [plate- bound anti- CD161 (- )] [no effect on proliferation]
[no effect on cytokine production] 11
CD4+ T cells Raji- LLT1 cells no effect on IFN- γ, TNF- α or IL- 2
production 5
P815- anti- CD161 (B199) no effect on IFN- γ or TNF- α production
P815- anti- CD161 (DX1) no effect on IFN- γ or TNF- α production
CD8+ T cells Raji- LLT1 cells no effect on IFN- γ or TNF- α
production
P815- anti- CD161 (B199) no effect on IFN- γ production decreased TNF- α production P815- anti- CD161 (DX1) no effect on IFN- γ production
decreased TNF- α production
[T cells] [anti- CD161 (- )] [no effect on proliferation]
CD4+CD161+ Th17 T- cell clones plate- bound anti- CD161 (HP3G10) increased IL- 17 production 7 CD8+ T cells from healthy and multiple
sclerosis donors plate- bound anti- CD161 (DX12) increased IFN- γ production 41
Vα7.2+IL- 18Rα++CD8+ T cells anti- CD161 (- ) no effect on cytotoxic activity 43
decreased IFN- γ, TNF- α and IL- 2 production
no effect on granzyme B production Vα7.2+CD8+CD3+ T cells biotin beads loaded anti- CD161
(191B8) increased IFN- γ and TNF- α production 29
CD161+ Treg cells biotin beads loaded anti- CD161
(191B8) increased IL- 10, IL- 17A, IL- 22 and
IL- 4 production 26
PLZF+CD4+ T cells from foetal small
intestine biotin beads loaded anti- CD161
(191B8) decreased IFN- γ and TNF- α
production 30
biotin beads loaded anti- CD161
(HP3G10) decreased IFN- γ and TNF- α
production CD4+CD161+ T cells biotin beads loaded anti- CD161
(HP3G10) no effect on IFN- γ or TNF- α
production CD161+Vα7.2- TCRαβ+CD4+ T cells biotin beads loaded anti- CD161
(HP3G10) no effect on IFN- γ or TNF- α
production
(Continues)
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WYROŻEMSKI AND QIAOexplain the variation in functional outcomes of CD161- mediated signalling and would enable to utilize the same CD161- LLT1 receptor- ligand interactions for different pur-poses within adaptive and innate immunity. In contrast, some studies suggested that signalling through CD161 is associ-ated with acid sphingomyelinase (ASM).36,40 ASM is known to be involved in controlling CD4+ T- cell responses through generation of ceramide, which exhibits multiple functions in a dose- dependent manner.48 For instance, ceramide was connected to the inhibition of T- cell proliferation and, at the same time, did not abrogate other TCR- mediated signals such as upregulation of activation markers CD69 or CD25.49 It is therefore plausible that the diversity and the magnitude of responses mediated by CD161 might be governed by endoge-nous ceramide levels. In any case, further work to investigate CD161 downstream signalling pathways is required in order to unravel the complexity behind co- signalling properties of CD161.
Overall, the lack of optimized method to study co- signalling through CD161 represents major limitation when examining the role of this receptor in T cells. Consequently, developing reliable system for functional analysis of CD161 would be valuable. Investigating CD161 in mice or rats is problematic as both species express multiple distinct NKR- P1 proteins with diverse functions and various degree of homol-ogy with human CD161.50 Therefore, reproducible in vitro models to study CD161 combined with thorough character-ization of anti- CD161 mAbs ought to be developed. A de-tailed review of NKR- P1 receptors in rodents was presented elsewhere.50 Although not discussed here, numerous studies showed that CD161+ T cells were enriched in various dis-ease conditions, thus suggesting their possible pathogenic or disease- driving character.12,15,20,36,41,45 As a result, CD161- expressing T cells are likely to play key role in various dis-eases, further supporting the need to fully examine biological and immunological uncertainties lying behind the expression of CD161 in T cells.
ACKNOWLEDGMENT
The project was supported by grant from Stiftelsen Kristian Gerhard Jebsen (project SKGJ- MED- 017).
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
AUTHOR CONTRIBUTIONS
LW design the study and wrote the manuscript; SW contributed to the study design, writing and critical review of the manu-script. LW and SW approved the final version of the manumanu-script.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
ORCID
Łukasz Wyrożemski https://orcid.
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Cell type CD161 ligation Results Reference
gluten- specific CD4+CD161+ T- cell
clones biotin beads loaded anti- CD161
(191B8) no effect on IFN- γ or IL- 21 production 45
unbound anti- CD161 (191B8) no effect on IFN- γ or IL- 21 production unbound anti- CD161 (HP3G10) no effect on IFN- γ production unbound anti- CD161 (HP3G10) no effect on proliferation
Note: Cells from peripheral blood of healthy adult donors were utilized unless otherwise specified. Clone of anti- CD161 antibody utilized in the study was indicated in round brackets whenever applicable. Data in square brackets were published as data not shown or unpublished observations.
TABLE 1 (Continued)
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39. Exley M, Porcelli S, Furman M, Garcia J, Balk S. CD161 (NKR- P1A) costimulation of CD1d- dependent activation of human T cells expressing invariant Vα24JαQ T cell receptor α chains. J Exp Med. 1998;188(5):867- 876.
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