The IL-17A-Producing CD8 + T-Cell Population in Psoriatic Lesional Skin Comprises Mucosa-Associated Invariant T Cells and Conventional T Cells

Abstract Efforts to establish an adeno-associated viral (AAV) vector-mediated gene therapy for the treatment of hemophilia B have been hindered by an immune response to the viral capsid antigen. Preclinical studies in small and large animal models of the disease showed long-term factor IX (F.IX) transgene expression and correction of the phenotype. However, in a recent phase I/II clinical trial in humans (Manno et al., Nat. Med. 2006), after hepatic gene transfer with an AAV-2 vector expressing human F.IX transgene, expression lasted for only a few weeks, declining to baseline concurrently with a peak in liver enzymes. We hypothesized that T cells directed towards AAV capsid antigens displayed by transduced hepatocytes were activated and these mediated destruction of the transduced hepatocytes, thereby causing loss of transgene expression and a transient transaminitis. Peripheral blood mononuclear cells isolated from AAV-infused subjects were stained with an AAV capsid-specific MHC class I pentamer either directly or after in vitro expansion. Two weeks after vector infusion 0.14% of circulating CD8+ T cells were capsid-specific on direct staining, and five weeks after infusion the capsid-specific population had expanded to 0.5% of the circulating CD8+ T cells, indicating proliferation of this T cell subset. By 20 weeks after vector infusion, the capsid-specific CD8+ T cell population had contracted to the level seen at 2 weeks. The expansion and contraction of this capsid-specific CD8+ T cell population paralleled the rise and fall of serum transaminases in the subject observed. Subsequent ex vivo studies of PBMC showed the presence of a readily expandable pool of capsid-specific CD8+ T cells up to 2.5 years post vector-infusion. Similarly, we were able to expand AAV-specific CD8+ T cells from peripheral blood of normal donors, suggesting the existence of a T cell memory pool. Expanded CD8+ T cells were functional as evidenced by specific lysis of HLA-matched target cells and by IFN-γsecretion in response to AAV epitopes. It has been argued that potentially harmful immune responses could be avoided by switching AAV serotypes, however, capsid protein sequences are highly conserved among different serotypes, as are some immunodominant epitopes that we identified. Indeed, we demonstrated that capsid-specific CD8+ T cells from AAV-infused hemophilic subjects functionally cross-react with AAV-8. Moreover, cells expanded from normal donors with AAV-2 vector capsids proliferated upon culture with AAV-8 capsids, demonstrating that both vectors could be processed appropriately in vitro to present the epitopic peptide to capsid-specific T cells. This suggests that AAV-2-specific memory CD8+ T cells normally present in humans likely would expand upon exposure to AAV-8 capsid epitopes. We conclude that the use of immunomodulatory therapy may be a better approach to achieving durable transgene expression in the setting of AAV-mediated gene therapy.

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A novel peripheral CD4+CD8+ T cell population: Inheritance of CD8α expression on CD4+ T cells

European Journal of Immunology ◽

10.1002/eji.1830270128 ◽

1997 ◽

Vol 27 (1) ◽

pp. 189-193 ◽

Cited By ~ 52

Author(s):

Marko Luhtala ◽

Olli Lassila ◽

Paavo Toivanen ◽

Olli Vainio

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Cd4 T Cells ◽

Cd8 T Cell

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Differentiation of a CD4/CD8αβ Double Positive T Cell Population from the CD8 Pool Is Both Predictive and Sufficient to Mediate Graft-Vs-Host Disease

Blood ◽

10.1182/blood-2021-147304 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2761-2761

Author(s):

Nicholas J. Hess ◽

David Turicek ◽

Amy Hudson ◽

Peiman Hematti ◽

Jenny Gumperz ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd8 T Cell ◽

T Cell Differentiation ◽

Cell Populations ◽

Human T Cell

Abstract Acute graft-vs-host disease (aGVHD) and cancer relapse remain the primary complications following an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for malignant blood disorders. While post-transplant cyclophosphamide combined with standard GVHD prophylaxis has greatly reduced the overall prevalence and severity of aGVHD, relapse rates remain a concern. There is thus a need to identify the specific human T cell populations mediating GVHD vs GVL activity as a means to develop targeted therapeutics capable of controlling aGVHD without inhibiting GVL activity. In this study, we identify a novel human T cell population that develops after transplant that is predictive and sufficient for GVHD pathology. To determine the role of human T cell populations in aGVHD, we performed xenogeneic transplantation studies using primary human graft tissue from a variety of sources (peripheral blood, G-CSF mobilized peripheral blood, bone marrow and umbilical cord blood) in addition to collecting primary human aGVHD blood samples from our clinic. Using the LD50 dose of human graft tissue, we identified a novel mature CD4 +/CD8αβ + double positive (DP) T cell population that only developed after transplantation. The development of this population was further confirmed in aGVHD patients from our clinic. The presence of DP T cells, irrespective of graft source, was also predictive of lethal GVHD in as early as one week after xenogeneic transplantation. To identify the origin of DP T cells, we transplanted isolated human CD4 or CD8 T cells into mice which showed that DP T cells only arise from the CD8 pool. Furthermore, re-transplantation of flow-sorted CD8 T cells from GVHD mice did not reveal a 2nd wave of DP T cell differentiation. This data, in addition to their highly proliferative state, suggests that DP T cells represent highly activated CD8 T cell clones. The ability of these CD8-derived DP T cells to gain CD4 expression coincides with their co-expression of both RUNX3 and THPOK, the master transcription factors of the CD8 and CD4 lineages respectively, that classically repress each other. Intracellular cytokine staining also revealed that DP T cells are the primary activated T cell population in xenogeneic GVHD, secreting both modulatory and cytotoxic cytokines (e.g. IFNγ, IL-17A, IL-22, perforin and granzyme). Ex vivo re-stimulation or re-transplantation of flow-sorted DP T cells showed that this T cell population is capable of dividing and expanding independent of CD4 and CD8 single positive T cells with the majority of the isolated DP T cells retaining their co-expression of CD4 and CD8. Finally, transplantation of either isolated human peripheral blood CD4 or CD8 T cell populations were capable of causing lethal GVHD. Conversely, re-transplantation of flow-sorted DP, CD8 or CD4 T cells from GVHD mice revealed that DP and CD4 T cells are sufficient to mediate GVHD pathology but re-transplanted CD8 T cell are not. This correlates with the absence of DP T cell differentiation in that re-transplanted CD8 population. The differentiation of DP T cells from chronically activated CD8 T cells represents a novel mechanism of GVHD pathology not previously described. The presence of DP T cells in other chronic inflammatory human diseases also suggests a broader pathology mediated by DP T cells. Further understanding of DP T cell differentiation and pathology may lead to targeted prophylaxis and/or treatment regimens for aGVHD and other human chronic inflammatory diseases. Figure 1 Figure 1. Disclosures Capitini: Nektar Therapeutics: Honoraria; Novartis: Honoraria.

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NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronic Toxoplasma gondii infection

10.1101/864272 ◽

2019 ◽

Author(s):

Daria L. Ivanova ◽

Ryan Krempels ◽

Stephen L. Denton ◽

Kevin D. Fettel ◽

Giandor M. Saltz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Nk Cells ◽

Cell Population ◽

Cd8 T Cells ◽

Nk Cell ◽

Chronic Phase ◽

Cd8 T Cell ◽

Cell Compartment

AbstractNK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and reduces parasite reactivation. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell behavior. This splenic CD49a-CD49b+NKp46+ NK cell population develops during the early chronic phase of infection and increases through the late chronic phase of infection. They are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. They are also absent from brain. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced. Blockade of NKp46 also rescued the chronically infected mice from death. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

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Clonal Expansion of Graft-Versus-Host Reactive CD8+ T Cells Is Dissociated from Full Effector Differentiation Following Delayed DLI.

Blood ◽

10.1182/blood.v110.11.2170.2170 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2170-2170

Author(s):

Ronjon Chakraverty ◽

Barry Flutter ◽

Hyeon-Seok Eom ◽

Farnaz Fallah-Arani ◽

Guiling Zhao ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Granzyme B ◽

Cd8 T Cell ◽

Host Environment ◽

Graft Versus Host ◽

Donor T Cells ◽

Ifn Γ

Abstract Extrinsic factors within the host environment are crucial in determining recruitment of graft-versus-host (GVH)-reactive T cells to peripheral tissues and the capacity of these cells to induce graft-versus-host disease (GVHD). In this study, we have examined how the host environment influences graft-versus-leukemia (GVL) activity. Transfer of small numbers of allogeneic T cells to freshly irradiated (TBI allo) mice induces both GVL and GVHD, whereas transfer of much higher numbers of T cells to established (>8 weeks) mixed chimeras (MC) can induce GVL without GVHD. Using an EL4 tumor protection assay and low doses of B10.A splenocytes (3 × 10e6, a dose 1 log lower than normally transferred to MC to induce GVL), we observed that tumor-free survival of recipient mice was greater following transfer to TBI allo B6 recipients than in B6 + B10.A → B6 MC. To determine the mechanisms for this disparity, we used a BALB/c recipient/B6 donor strain combination, in which we could track the distribution of donor T cells within secondary lymphoid organs and bone marrow (BM) following transfer to TBI allo or MC recipients. Despite similar expansions within the spleen, there was a significant delay in the accumulation of polyclonal donor T cells (B6 CD45.1) and transgenic 2C GVH-reactive CD8+ T-cells (bearing TCR specific for recipient antigen) in the BM of MC compared to TBI allo mice. Moreover, in vivo cytotoxicity of host B cell targets occurred rapidly and was virtually complete in TBI allo recipients, but was absent in MC even at late time points. To evaluate the acquisition of effector functions in a clonal GVH-reactive CD8+ T cell population, we sorted 2C T cells at intervals following transfer and performed quantitative RT-PCR of molecules linked to effector differentiation. Strikingly, transcription of IFN-γ, granzyme B and TNF-α was significantly higher in cells derived from TBI allo hosts compared to MC. Similar differences in IFN-γ and granzyme B protein expression were confirmed in the polyclonal donor CD8+ T cell population. Since, full GVL activity might also depend upon the survival of GVH-reactive CTL, we also examined the viability of donor T cells during the initial response in both environments. We observed higher rates of sustained 2C CD8+ T cell apoptosis (as indicated by annexin V staining) following T cell transfer to MC. Furthermore, we also detected lower expression of common γ chain cytokine receptors that mediate responsiveness to IL-2, IL-7 and IL-15, upon donor T cells from MC. However, following secondary co-transfer to syngeneic recipients for 21 days, memory phenotype polyclonal donor CD8+ T cells derived from established MC (CD45.1+) were recovered to a greater extent than T cells initially derived from TBI allo mice (Thy1.1+), arguing against any intrinsic defect in the viability of GVH-reactive T cell populations emerging in the former setting. Indeed, when co-cultured in the presence of individual cytokines, MC-derived CD8+ T cells maintained viability to a greater (IL-2, IL-7) or equivalent (IL-15) extent as TBI allo-derived cells. Taken together, these data suggest that disparity in GVL activity following to TBI allo recipients and MC can be explained by differences in the effector function and survival of anti-host CTL in quiescent MC environment. Reduced GVL activity of donor T cells on a per-cell basis in MC can be compensated for by transferring greater numbers of cells.

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Gamma Interferon Regulates Contraction of the Influenza Virus-Specific CD8 T Cell Response and Limits the Size of the Memory Population

Journal of Virology ◽

10.1128/jvi.01776-13 ◽

2013 ◽

Vol 87 (23) ◽

pp. 12510-12522 ◽

Cited By ~ 16

Author(s):

Nayana Prabhu ◽

Adrian W. Ho ◽

Kenneth H. S. Wong ◽

Paul Edward Hutchinson ◽

Yen Leong Chua ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Cell Response ◽

Memory Cell ◽

Cd8 T Cell ◽

T Cell Response ◽

Ifn Γ

The factors that regulate the contraction of the CD8 T cell response and the magnitude of the memory cell population against localized mucosal infections such as influenza are important for generation of efficient vaccines but are currently undefined. In this study, we used a mouse model of influenza to demonstrate that the absence of gamma interferon (IFN-γ) or IFN-γ receptor 1 (IFN-γR1) leads to aberrant contraction of antigen-specific CD8 T cell responses. The increased accumulation of the effector CD8 T cell population was independent of viral load. Reduced contraction was associated with an increased fraction of CD8 T cells expressing the interleukin-7 receptor (IL-7R) at the peak of the response, resulting in enhanced numbers of memory/memory precursor cells in IFN-γ−/−and IFN-γR−/−compared to wild-type (WT) mice. Blockade of IL-7 within the lungs of IFN-γ−/−mice restored the contraction of influenza virus-specific CD8 T cells, indicating that IL-7R is important for survival and is not simply a consequence of the lack of IFN-γ signaling. Finally, enhanced CD8 T cell recall responses and accelerated viral clearance were observed in the IFN-γ−/−and IFN-γR−/−mice after rechallenge with a heterologous strain of influenza virus, confirming that higher frequencies of memory precursors are formed in the absence of IFN-γ signaling. In summary, we have identified IFN-γ as an important regulator of localized viral immunity that promotes the contraction of antigen-specific CD8 T cells and inhibits memory precursor formation, thereby limiting the size of the memory cell population after an influenza virus infection.

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Memory T cells in cancer immunotherapy: which CD8+T-cell population provides the best protection against tumours?

Tissue Antigens ◽

10.1111/j.1399-0039.2008.01088.x ◽

2008 ◽

Vol 72 (3) ◽

pp. 187-194 ◽

Cited By ~ 40

Author(s):

R. Perret ◽

F Ronchese

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Immunotherapy ◽

Cell Population ◽

Memory T Cells ◽

Cd8 T Cell

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CMV-Specific CD8+ T-CELL Function Is NOT Impaired In CLL

Blood ◽

10.1182/blood.v122.21.2862.2862 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2862-2862

Author(s):

Doreen te Raa ◽

Fernanda Pascutti ◽

Juan J Garcia-Vallejo ◽

Emilie Reinen ◽

Ester B.M. Remmerswaal ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Conflicts Of Interest ◽

Cd8 T Cell ◽

Laser Scanning Microscopy ◽

Functional Changes ◽

Lower Expression

Abstract Introduction T-cell exhaustion is a state of acquired T-cell dysfunction that arises during chronic infections, but also in the presence of cancer. Chronic lymphocytic leukemia (CLL)-derived CD8+ T cells were recently found to exhibit features of exhaustion as shown by increased expression of inhibitory receptors (including PD-1), impaired proliferative and cytotoxic capacity and disturbed immunological synapse (IS) formation (Riches et al, Blood ’13). In contrast, we have reported a decreased expression of PD-1 on effector-type CD45RA+/-CD27- CD8+ T cells in CLL patients (Tonino et al., Leuk&Lymph ‘12). As this population is enriched for CMV-specific T cells, this implies that PD-1 expression might also be decreased on CMV-specific T cells. Importantly, CMV viral loads are generally undetectable in untreated CLL patients. Taken together these data suggest that the phenotypical and functional changes found in the total CD8+ T-cell population in CLL may not be applicable to CMV-specific CD8+ T cells. In this study, we have thoroughly analyzed phenotype and function of CMV-specific CD8+T cells in CLL. Methods and Results In agreement with Riches et al. we found an increased expression of the exhaustion markers PD-1, CD160 and CD244 (assessed by flow cytometry) on CLL-derived total CD8+ T cells (n=38) as compared to CD8+ T cells from age-matched healthy controls (HC; n=13). In sharp contrast, we found a significantly lower expression of these markers on CMV-tetramer+CD8+ T cells in CLL patients (n=18) as compared to HC (n=7). Next we analyzed the functionality of CMV-specific CD8+ T cells derived from CLL patients and HC. First, the sensitivity of the functional assays used was verified by treating CD8+ T cells with cyclosporine, which mimics intrinsic T-cell defects in vitro. Cytokine production was measured upon stimulation with PMA/Ionomycin. We found no differences between CLL patients and age-matched HC as to IFNγ, TNFα and IL-2 production by CMV-tetramer+CD8+ cells. Interestingly, the fraction of CMV-tetramer+CD8+ T cells producing cytokines after stimulation with CMV-pp65-peptide loaded EBV-transformed B-lymphoblastoid cell lines (EBV-LCLs) derived from normal B lymphocytes also did no differ between CLL patients and HC. Next, the cytotoxic potential of these cells was examined. CMV-specific CD8+ T cells from CLL patients were as effective as those from HC in killing CMV-peptide-loaded EBV-LCLs at varying effector:target ratios. Finally, CMV-specific IS formation was assessed by imaging flow cytometry analysis. This technique combines quantitative and qualitative data and has advantages over the current gold standard in the study of IS, i.e. confocal laser-scanning microscopy, since it is able to measure large cell populations in an automated fashion. On average 0.6x105 total cells per condition were acquired containing approximately 550 doublets. Again, percentages of CD8+T cells forming specific proper IS with CMV-peptide loaded EBV-LCLs were comparable in CLL and HC T cells (around 45%). Conclusion In contrast to evidence for a global disturbed T-cell functionality in CLL, characterized by T cells exhibiting phenotypic and functional signs of exhaustion, we now show that CMV-specific CD8+ T cells derived from CLL patients have a lower expression of exhaustion markers and are functionally intact. These data shed new light on the complexity of interactions between T-lymphocytes and CLL cells and indicate that changes found in the total CD8+ T-cell population in CLL cannot be extrapolated to CMV-specific CD8+ T cells. Disclosures: No relevant conflicts of interest to declare.

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Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2008571117 ◽

2020 ◽

Vol 117 (41) ◽

pp. 25667-25678 ◽

Cited By ~ 1

Author(s):

J. Justin Milner ◽

Hongtuyet Nguyen ◽

Kyla Omilusik ◽

Miguel Reina-Campos ◽

Matthew Tsai ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Human Peripheral Blood ◽

Cd8 T Cell ◽

Effector Memory ◽

Lymphoid Tissues ◽

Phenotype Classification ◽

Memory Cd8 T Cell

Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated that circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was terminally fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection. Notably, this terminally differentiated effector memory CD8 T cell population (terminal-Tem)was conflated within the conventional Tempopulation, prompting redefinition of the classical characteristics of Temcells. Murine terminal-Temwere transcriptionally, functionally, and developmentally unique compared to Temcells. Through mass cytometry and single-cell RNA sequencing (RNA-seq) analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-Tempopulation of CD8 T cells that was transcriptionally distinct from Temand Tcm. Key findings from this study show that parsing of terminal-Temfrom conventionally defined Temchallenge the reported characteristics of Tembiology, including enhanced presence in lymphoid tissues, robust IL-2 production, and recall potential, greater than expected homeostatic fitness, refined transcription factor dependencies, and a distinct molecular phenotype. Classification of terminal-Temand clarification of Tembiology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.

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DOP70 High-dimensional analysis reveals a novel signature for IL-17 producing CD8 T cells in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.109 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S106-S107

Author(s):

A M Globig ◽

P Otto-Mora ◽

A Hipp ◽

M Heeg ◽

H Schwacha ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Cd8 T Cells ◽

Peripheral Blood ◽

T Cell Responses ◽

Cd8 T Cell ◽

Intestinal Tissue ◽

Cell Responses ◽

Distinct Cell

Abstract Background The pathogenesis of IBD has previously mainly been associated with a dysregulation of CD4 T-cell responses, and active disease is linked to induction of pathogenic IL-17 producing T helper cells. Importantly, CD8 T cells can also produce IL-17 and demonstrate a significant increase in active IBD. However, it remains unclear whether this is due to conventional or unconventional T-cell responses and whether these CD8 responses could play a role as novel biomarkers or therapeutic targets of active IBD. Methods We isolated lymphocytes from the peripheral blood and intestinal tissue of IBD patients (n = 56) and performed a detailed analysis of CD8 T-cell phenotype and function using high-parametric flow cytometry and mass cytometry in combination with algorithm-aided bioinformatic analysis. Results We observe a significant increase in IL-17 production by CD8 T cells in active IBD, primarily produced by conventional CD8 T cells. Unconventional T-cell subsets (e.g. MAIT cells, γδ T cells and NKT cells) represented only ~30% (peripheral blood) or ~25% (intestinal tissue) of IL-17 producing CD8 T cells (Tc17). The mass cytometric analysis identified Tc17 cells as a distinct cell population within the intestinal CD8 T-cell compartment that can be further subdivided into 3 subsets which share expression of phenotypic markers such as CD6, CD39, CD69 and PD1 and a low expression of CD27. This novel signature was validated in a separate cohort of IBD patients. Moreover, at initial IBD diagnosis, the IL-17 signature is associated with flare-free survival in a retrospective cohort analysis based on published transcriptome data. Conclusion Our data indicate that conventional IL-17 producing CD8 T cells are a very distinct cell population that is linked to IBD activity. The identification of a novel IL-17 CD8 signature may help guide treatment decisions as a biomarker and for immunotherapeutic approaches.

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