MHC – Major Histocompatibility Complex
TCR – T Cell Receptor
iNKT – Natural Killer T
MAIT – Mucosal Associated Invariant T
NK – Natural Killer
KIR – Killer Immunoglobulin-like Receptor
IM – Innate Memory
VM – Virtual Memory
MPLA – Monophosphoryl Lipid A
PBMCs – Peripheral Blood Mononuclear Cells
ITIMs- Immunoreceptor Tyrosine-based Inhibitory Motifs
ITAMs – Immunoreceptor Tyrosine-based Activating Motifs
SLAM – Signalling Lymphocytic Activation Molecule
EBV – Epstein-Barr Virus
CML-CP – Chronic Phase of Chronic Myeloid Leukemia.
RRR – Pattern Recognition Receptors
PAMPs – Pathogen/damage Associated Molecular Patterns
pMHC – peptide-MHC Complex
IFN – Type I Interferon
SHP1 or 2 – Src Homology 2 domain containing Phosphatases
CRACC – CD2-like Receptor Activating Cytotoxic Cells
HIV – Human Immunodeficiency Virus
AIDS – Acquired Immuno Deficiency Syndrome
PD-1 – Programmed Death 1
KLRG1 – Killer Cell Lectin-like Receptor G1
The immune system has traditionally been subdivided into two arms, the innate and adaptive immune systems.The innate immune system is the first responder against foreign invaders, and acts rapidly in a non-specific manner to clear infections as quickly as possible. This rapid response is triggered by signalling events that are initiated by Pattern Recognition Receptors (PRRs) that recognise Pathogen/damage Associated Molecular Patterns (PAMPs) or self-molecules. The innate immune system is evolutionarily older than the adaptive immune systems, inherently present in most vertebrates and non-vertebrates, and is composed of physical and chemical barriers, phagocytic leukocytes, dendritic cells, natural killer (NK) cells, and plasma proteins1. The adaptive immune system on the other hand takes a longer time to generate a response against an infection, but it is more potent and highly specific to the foreign invader than the innate immune response. A key feature of the adaptive immune system is that it has the capacity to develop immunological memory, which helps protect against recurrent infections. The adaptive immune system is evolutionarily a more recent development, found exclusively in vertebrates and consists of T cells and B cells1. However, there has been a growing realization over the past two decades that the innate and adaptive immune systems are not as distinct as was initially believed. It is now known that there are several cell types that have functional characteristics of both systems, and that they essentially bridge these two branches. The existence of several subsets of unconventional T cells is an example of such cell types.
Conventional CD8+ T cells have constitutive cytotoxic activity and are responsible for killing infected/abnormal cells. They do this by recognising specific antigen peptides presented to them by cell-surface proteins of the Major Histocompatibility complex (MHC) I family, accompanied by co-stimulation and in the presence of appropriate cytokines. NK cells also have a crucial function in killing virus infected and tumour-transformed cells. However, unlike CD8+ T cells, NK cells utilize germ line encoded receptors that recognize missing self or altered self on the surface of a target cell in order to carry out their effector function. These NK cell receptors, which can be activating or inhibitory, are not restricted to NK cells and are also expressed on certain T cell subsets. These T cells are collectively known as unconventional T cells. They are not donor restricted, and can recognize antigens presented by non-polymorphic antigen-presenting molecules such as those encoded by genes within the MHC locus (HLA-E, HFE, H2-M3 and H2-Q9) or those encoded by genes outside the MHC locus (CD1a, CD1b, CD1c, CD1d and MR1)2. Functionally, these unconventional T cells are poised to rapidly respond, and can be activated by both T cell receptor (TCR) ligation as well as danger signals and pro-inflammatory cytokines in a TCR independent fashion3. These populations of unconventional T cells include not only T cells, natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells but also the recently described human NK-like CD8 T cells4.
NK-like CD8+ T cells were first described in the early 2000s in studies conducted in both mice and humans, and were shown to be different to NKT cells which are CD1d restricted and have a semi-invariant TCR. These NK-like T cells co-expressed a TCR and natural killer (NK) cell receptors including CD56, killer cell immunoglobulin-like receptors (KIR), CD94, NKG2A, and NKG2C5,6 (Figure 1). There is still a gap in the knowledge with respect to the specifics of the generation and differentiation processes associated with these cells but type I interferon (IFN), IL-4 and IL-15 have been shown to influence the same in mice4 <Sounds odd to me – influence the same in mice. What same?>. Studies in done in humans, on the role of these factors, are limited. There is more evidence in the literature regarding the phenotype of these cells in terms of the different receptors that these cells express, which shall be discussed further in the subsequent sections.
Figure 1: Diagrammatic comparison between a Conventional T cell and an NK-like T cell. Michel, J.J. et al. Front.Immunol.7, 530 (2016).
NK cell receptors
Prior to examiningthe phenotype of NK-like CD8+ T cells, it is important to understand the function of various NK cell receptors. This section takes a closer look at the various NK cell receptors commonly found on NK-like CD8+ T cells. The scope of the following discussion will, however, be limited to the receptors that were used as markers for the present study. Understanding NK cell receptors, their ligands, and general downstream signalling is of great importance given that NK cell responses are controlled by the balance of signalling through multiple activating and inhibitory cell surface receptors and would result in similar response when expressed on CD8+ T cells. NK cell receptors, unlike a TCR, are not highly antigen specific. They are germ line encoded, can be activating or inhibitory, or both, and are reported to be promiscuous with respect to ligand binding 7. They are grouped into families on the basis of similar recognition receptors as outlined below. Table 1 summarises the details of the various individual receptors within these families.
KIR Family Receptors
Members of the KIR family of receptors have evolved from the Ig-superfamily and consist of a trans-membrane domain, two or three Ig-like domains and a cytoplasmic tail 7.They can either by activating or inhibitory. Inhibitory KIRs have been implicated in inhibiting cytokine release and target cell cytolysis in effector T cells8. Inhibitory KIRs signal through intracellular Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs), which are located on the cytoplasmic tails of these receptors. On being stimulated, the receptor recruits Src homology 2 domain containing phosphatases (SHP1 or 2) followed by downstream signalling9. Activating KIRs signal through DAP-12 7. While the exact sequence of signalling events are not well characterized, DAP-12 signalling are distinct, wherein the former results in cytotoxicity and the latter results in cytokine secretion and cytotoxicity10. KIRs specifically bind HLA-A, HLA-B and HLA-C and recognize polymorphisms in these molecules7. This binding of the KIR to the HLA molecule is also influenced by the peptide bound to the HLA molecule11. Despite these similarities between KIR and TCR recognition of the peptide-MHC Complex (pMHC), the region of the ligands recognized by the two receptors, peptide specificity, the downstream signalling and physiological responses initiatedby both receptors are very different12.
CD94-NKG2 Heterodimer Receptors
CD94-NKG2A/C/E heterodimers are a family of C-type lectin receptors. These receptors recognize non-classical MHC class I molecules (HLA-E in humans) on the surface of potential target cells13. HLA-E binds peptides derived from the leader sequence of MHC class I molecules on target cells and thus allows CD94-NKG2A and CD94-NKG2C to indirectly monitor the expression of MHC class I molecules on the cell13. CD94-NKG2A in humans is inhibitory and thought to be a key player in preventing inappropriate NK cell activation and inhibiting antigen-specific effector functions in T cells8,14. The other receptors in this family are stimulatory, and whether or not they possess the ability to modulate T cell function is still not known15. In humans, expression of these receptors may be inversely related to KIR expression as NK cell clones that lack inhibitory KIR expression were shown to express an inhibitory CD94-NKG2 heterodimer16.
Signalling Lymphocytic Activation Molecule (SLAM) Receptors
Members of this family include 2B4 and CD2-like receptor activating cytotoxic cells (CRACC). They possess two Ig-like domains – one variable (V)-like domain and one constant 2 (C2)-like domain, a transmembrane domain and a cytoplasmic tail bearing multiple tyrosine-based motifs17. SLAM-related receptors are typically self-ligands with the exception of 2B4, which interacts with CD48 17.The NK cell receptor CD244 (2B4) on being stimulated, recruits the adaptor proteins SAP or ERT, which contain Src homology 2 domains, by means of an immunoreceptor tyrosine-based switch motif present in the cytoplasmic tail18. This results in downstream signalling being initiated
|Killer immunoglobulin-like receptors (KIR) family|
|KIR2DL1 (p58.1)||HLA-Cw2, 4, 5, 6||NK, T cells||Inhibitory|
|KIR2DL2 (p58.2)||HLA-Cw1, 3, 7, 8||NK, T cells||Inhibitory|
|KIR3DL1 (p70)||HLA-Bw4||NK, T cells||Inhibitory|
|KIR3DL3 (p140)||HLA-A3, -A11||NK, T cells||Inhibitory|
|KIR2DS1 (p50.1)||HLA-Cw2,4,5,6||NK, T cells||Stimulatory|
|KIR2DS2 (p50.2)||HLA-Cw1,3,7,8||NK, T cells||Stimulatory|
|KIR2DS4 (p50.3)||Unknown||NK, T cells||Stimulatory|
|SLAM receptor family|
|2B4 (CD244)||CD48||All NK cells ,a CD8+ T cell subset and monocytes||Inhibitory/Stimulatory|
|CRACC||Homophilic||CTL, activated B cells, NK cells and mature DCs||Inhibitory/Stimulatory|
Table 1: Human NK cell receptors ligands and function19. Adapted from Wu, et al Front biosci10, 3132-3142 (2005).
Phenotypic characteristics of NK-like CD8+ T cells
NK-like CD8+ T cells have been described using many different names including CD56+ CD8+ NKT-like cells and KIR+ CD8+ T cells, Effector memory CD8+ T cells that express NK cell receptors have been referred to as innate like CD8+ T cells. This section attempts to look more closely at the various studies conducted on NK-like CD8+ T cells in both mice and humans in order to understand their phenotype.
CD8+ T cells producing IFN in response to innate signals in a TCR independent fashion were described in mice roughly at the same time as NK-like CD8+ T cells were being described in humans4,20. These cells possessed a memory phenotype (CD44+, CD62L-, CD122+) and were shown to provide protection against infections caused by Listeria monocytogenes21. This work was closely followed by the identification of a population of thymic CD8+ T cells called innate memory (IM) CD8+ T cells that responded to IL-12 and IL-18 by producing IFN4,22. A similar population of cells were also described in mouse spleen and peripheral lymphoid organs, and were called virtual memory (VM) CD8+ T cells4,23. Both IM and VM CD8+ T cells possess a memory phenotype (CD44+, CD62L-) and their differentiation has been demonstrated to be dependent on Eomes and IL-1522,23. IM and VM CD8+ T cells have been differentiated from each other on the basis of expression of the integrin CD49d by mouse thymic IM CD8+ T cells4. Wang et al. defined NK-like CD8+ T cells in mice asTCR+ CD3+ NK1.1+ CD49b+ NKG2D+ cells and described their ability to secreteIFN when stimulated with dendritic cells24. Yet another study in mice defined NK-like CD8+ T cells purely on the basis of their memory phenotype (CD44+, CD62L-), and described the activation and expansion of these cells in response to co-administration of -GalCer and the TLR4 agonist monophosphoryl lipid A (MPLA)25.
NK-like CD8+ T cells in humans were characterised by several studies as possessing a TEMRA (CD45RA+, CCR7-, CD57+) phenotype26. Evidence went on to show that these KIR+ CD8+ TEMRAcells appeared to have fewer different V when compared to their negative counterparts26. This skewing within the KIR+ CD8+ TEMRA population is suggestive of such cells having undergone a phase of expansion after acquisition of the KIR, possibly as a result of prolonged antigenic pressure4,26. These KIR+ CD8+ cells also had a weaker response to TCR stimulation than their KIR- counterparts in terms of expression of IFN, TNF and degranulation, which was evaluated by CD107a staining26. This subset of cells however responded very well to innate cytokine stimulation with IL-12 and IL-1827. Different groups have chosen to define NK-like CD8+ T cells differently in each of their respective studies. In a study looking at the expression of inhibitory NK-receptors in human melanoma–specific CD8+ T cells, melanoma antigen specific TCR+ CD8+ cells were studied and the percentage of NK-receptor positive (p58.1, p58.2, p70, p140, ILT2, NKRP1A, ZIN176, CD94 and CD94/NKG2A) T cells were assessed28. These cells were shown to have anterminally differentiated phenotype (CD28-, CD57+)28. Hassounehet al. chose to define NK-like CD8+ T cells as CD57+ CD56+ CD8+ T cells in his study looking at these cells in the context of Cytomegalovirus (CMV)29. Yet another study on NK-like CD8+ T cells defined these cells as KIR+ and/or NKG2A+ CD8+ T cells and showed that they preferentially expressed Eomes, had a memory phenotype, and shared functional and phenotypic features with IM CD8+ T cells in mice30. These cells also preferentially expressed CD57 and CD49d4,30. CD49d is an α4-integrin, which is important in determining the localization of T cells to different territories based on the β chain to which it is matched4. In NK-like CD8+ T cells however, its use as a functional marker has been proposed making it a possible characteristic marker for these cells4. The aforementioned studies describe a variety of NK cell receptors that are expressed on T cells. It is however essential to realize that the NK cell repertoire that is expressed on NK-like CD8+ T cells express does not reflect the full complement of NK receptors expressed on NK cells31. While there is no clear cut definition of NK-like CD8+ T cells, it appears that they can be best defined as CD8+ T cells that express NK receptors, have impaired TCR signalling, display a memory phenotype, express Eomes and respond to innate cytokine stimulation (IL-12 and IL-18) by producing IFN (see Figure 2).
Figure 1. Representative diagram of a human NK-like CD8+ T cell detailing the most commonly used markers and nuclear transcription factors that assist in defining this unique subpopulation of cells. These cells also respond to IL-12 and IL-18 innate-like stimulation and produce IFN. Adapted from Barbarin, A. et al.Front. Immunol.8, 316 (2017).
NK-like CD8+ T cells in Immunosenescence and Viral Infections
Immunosenescence refers to the faulty immune response seen during aging, that occurs because of general decline in immune function38. Aging sees a steady decline in the number of naïve T cells emerging from the thymus, but this is accompanied by an increase in the number of memory T cells that undergo significant changes in phenotype and function especially CD8+ T cells3,39. A hallmark characteristic of aging T cells is the loss of co-stimulatory receptors such as CD28 and CD274,40. This loss or absence of co-stimulatory receptors is believed to be the reason for deficiency or ineffective TCR signalling in aged T cells. An increase in the number of effector/senescent T cells expressing NK markers has also been reported to be associated with aging41. Evidence clearly shows that there is differential regulation of NK cell receptor expression between T cells and NK cells42. For example, expression levels of CD158b1 (KIR 2DL2) in NK cells and T cells have been reported as being controlled by two distinct transcriptional regulatory motifs on the upstream cis-acting promoter region of the gene43. This suggests that expression of NK receptors on T cells is not a random event associated with aging, but that it is actually a physiologically programmed phenomenon. This acquisition of a diverse array of NK receptors by inefficiently functioning T cells, helps maintain immunologic diversity in old age. It also helps to compensate for any loss in the NK cell compartment, which might occur due to skewing of NK cell subsets with aging44. It appears that the age-dependent appearance of functionally competent senescent NK-like CD8+ T cells represents an overall beneficial remodelling of the immune repertoire38. It is however important to keep in mind that aging is a process that is unique to an individual and results in highly heterogeneous health and immune phenotypes being observed within a cohort being studied making extrapolatingand discussing results a challenge.
NK-like CD8+ T cells and Disease associations
An increase in percentage of frequency of NK-like CD8+ T cells has been described in individuals suffering from disease conditions such as Behcet’s Uveitis and Leishmaniasis<please check that I have corrected these names properly> where they produce more IFN- compared to healthy individuals, and in chronic obstructive pulmonary disease where they produce IFN and TNF32-34. NK-like CD8+ T cells have also been described as potentially having an anti-cancer role. This can be inferred, indirectly, on the basis of studies conducted in patients in the chronic phase of chronic myeloid leukemia (CML-CP). These patients have been shown to have major defects in their NK-like CD8+ T cells when compared with healthy subjects or patients in complete remission. The defects manifest as a loss of IFN-γ expression in response to innate cytokine stimulation by IL-12 and IL-18,and loss of degranulation after stimulation via CD1635. However, IFN-γ expression after TCR stimulation by the same NK-like CD8+ T cells during CP was conserved, which indicates that the functional defect affecting NK-like CD8+ T cells is innate rather than adaptive35. The implications of this defect, with respect to understanding functionality of these cells, are yet to be investigated. The presence of these NK-like CD8+ T cells was also detected in solid tumours such as lymph nodes invaded by tumour cells in metastatic breast cancer, and amongst intra-tumoural lymphocytes in ovarian cancer4. These studies provide evidence that NK-like CD8+ T cells are present not only in tumours, but that they are also probably intimately integrated in the dynamics of anticancer responses.
NK-like CD8+ T cells in Epstein-Barr virus (EBV) associated tumour patients were shown to be quantitatively and functionally impaired36. Women suffering from Human Papilloma virus (HPV) associated cervical neoplasia showed increased levels of CD28-, TEM and CD16+ CD56+ CD8+ T cells amongst their PBMCs, which is probably a result of the chronic HPV infection37. From these studies it can be inferred that NK-like CD8+ T cells interact with other cells and their phenotype is greatly influenced by the type of chronic antigenic stimulation they experience.
Several reports state that one of the main drivers responsible for the accumulation of highly differentiated antigen specific CD8+ T cells that display characteristics of replicative senescence, is persistent viral infections such as CMV and EBV, which cause chronic immune activation3,45,46.The studies pertaining to CMV however, are purely associative and not causal. Further, these studies involved a cohort of individuals that were belonged to an elderly population. Thus the causative role of CMV in inducing expansion of senescent NK-like CD8+ T cells remains to be proven. The current hypothesis being proposed is that NK-like CD8+ T cells accumulate with age in CMV seropositive individuals as opposed to CMV infection per se47. However, the expansion of CD57+ CD8+ T cells is a hallmark of latent CMV infection, where CD57+ T cells display a reduced capacity to proliferate accompanied with altered functional properties48,49. Furthermore, NK-like CD8+ T cells in CMV seropositive individuals are also largely CD57+ thus implying that they are mostly senescent29.
NK-like CD8+ T cells in HIV-1 infected individuals
The human immunodeficiency virus (HIV), which is responsible for causing Acquired Immuno Deficiency Syndrome (AIDS), is one of the world’s most serious health and development challenges. As of 2016, an estimated 36.7 million people worldwide were living with HIV/AIDS50. Of these, 2.1 million were children (<15 years old). HIV-1 predominantly replicates in CD4+ T cells , both in the early and late stages of the disease. The early/primary stage of HIV infection sees titre levels of the virus reach peak levels; the viremia, however, stabilizes around 3 to 6 months later as a result of partially being controlled by the immune response51. CD8+ cytotoxic T cells are especially important in the clearance of HIV infected cells and help control the infection. However, CD8+ T cell responses in chronic HIV-1 infection are relatively impaired which results in inefficient clearance of the virus52. The abnormalities/defects seen in HIV-1 infected CD8+ T cells are similar to those seen in CD8+ T cells during aging which is relatively unsurprising given that HIV infected individuals experience accelerated immunosenescence 53. CD8+ T cells in HIV infected individuals express increased levels of the inhibitory receptor programmed death 1 (PD-1) and the killer cell lectin-like receptor G1 (KLRG1), which are markers for exhaustion and immunosenescence respectively54,55.
A limited amount is known about NK-like CD8+ T cells in HIV-1 infected individuals. A few studies have described KIR+ CD8+ T cells in HIV-1 infected individuals as a population of cells that are largely non-responsive to TCR dependent stimulation56-58. These studies have also demonstrated that KIR expression on CD8+ T cells is associated with a reduced ability to kill target cells. These cells have also been shown to predominantly be memory CD8+ T cells. Another study has gone on to describe a generalized suppression of TCR-mediated activity of KIR+ CD8+ T cells during HIV-1 infection via a ligand-independent blockade of TCR activation. The phenotype and function of these cells needs to be further assessed.
The main aim of this project was to define and phenotypically characterize NK-like CD8+ T cells in HIV-1 chronically infected individuals using flow cytometry on the basis of expression of NK cell receptors, memory phenotype, exhaustion markers, transcriptional profile and TCR usage. We also set out to understand their functional properties by investigating their response to innate cytokine stimulation. This project was aimed at providing insight into the relevance of these cells in the context of HIV infection and providing preliminary data towards investigating the possibility of these cells as an immunotherapeutic.
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6 Arlettaz, L. et al. Activating CD94:NKG2C and inhibitory CD94:NKG2A receptors are expressed by distinct subsets of committed CD8+ TCR alphabeta lymphocytes. European journal of immunology34, 3456-3464, doi:10.1002/eji.200425210 (2004).
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15 Carretero, M. et al. The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. European journal of immunology27, 563-567, doi:10.1002/eji.1830270230 (1997).
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25 Coelho-Dos-Reis, J. G. et al. Co-administration of alpha-GalCer analog and TLR4 agonist induces robust CD8(+) T-cell responses to PyCS protein and WT-1 antigen and activates memory-like effector NKT cells. Clin Immunol168, 6-15, doi:10.1016/j.clim.2016.04.014 (2016).
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34 Hodge, G., Hodge, S., Reynolds, P. N. & Holmes, M. Targeting peripheral blood pro-inflammatory CD28null T cells and natural killer T-like cells by inhibiting CD137 expression: possible relevance to treatment of bronchiolitis obliterans syndrome. J Heart Lung Transplant32, 1081-1089, doi:10.1016/j.healun.2013.07.017 (2013).
35 Jacomet, F. et al. The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia. Frontiers in immunology7, 688, doi:10.3389/fimmu.2016.00688 (2016).
36 Xiao, W. et al. EBV-induced human CD8(+) NKT cells synergize CD4(+) NKT cells suppressing EBV-associated tumors upon induction of Th1 bias. Cellular and Molecular Immunology8, 368-368, doi:10.1038/cmi.2011.66 (2011).
37 Pita-Lopez, M. L., Ortiz-Lazareno, P. C., Navarro-Meza, M., Santoyo-Telles, F. & Peralta-Zaragoza, O. CD28-, CD45RA(null/dim) and natural killer-like CD8+ T cells are increased in peripheral blood of women with low-grade cervical lesions. Cancer Cell Int14, 97, doi:10.1186/s12935-014-0097-5 (2014).
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49 Pera, A. et al. CMV latent infection improves CD8+ T response to SEB due to expansion of polyfunctional CD57+ cells in young individuals. PloS one9, e88538, doi:10.1371/journal.pone.0088538 (2014).
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