scholarly journals HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

2019 ◽  
Vol 16 (4) ◽  
pp. 302-314
Author(s):  
Chinnambedu Ravichandran Swathirajan ◽  
Ramachandran Vignesh ◽  
Greer Waldrop ◽  
Uma Shanmugasundaram ◽  
Pannerselvam Nandagopal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Activation Rates ◽  
Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

scholarly journals Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation

2018 ◽  
Author(s):  
Dafni A. Glinos ◽  
Blagoje Soskic ◽  
Luke Jostins ◽  
David M. Sansom ◽  
Gosia Trynka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Memory T Cells ◽  
Cd4 T Cell ◽  
Genomic Profiling ◽  
Memory Cells ◽  
Cell Responses

SummaryT cell activation is a critical driver of immune response and if uncontrolled, it can result in failure to respond to infection or in excessive inflammation and autoimmunity. CD28 costimulatory pathway is an essential regulator of CD4 T cell responses. To deconvolute how T cell receptor (TCR) and CD28 orchestrate activation of human CD4 T cells we stimulated cells using varying intensities of TCR and CD28 signals followed by gene expression profiling. We demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Strikingly, cell cycle and cell division are sensitive to CD28 in memory cells, but under TCR control in naive cells, in contrast to the paradigm that memory cells are CD28-independent. Using a combination of chromatin accessibility and enhancer profiling, we observe that IRFs and Blimp-1 (PRDM1) motifs are enriched in naive and memory T cells in response to TCR. In contrast, memory cells initiate AP1 transcriptional regulation only when both TCR and CD28 are engaged, implicating CD28 as an amplifier of transcriptional programmes in memory cells. Lastly, we show that CD28-sensitive genes are enriched in autoimmune disease loci, pointing towards the role of memory cells and the regulation of T cell activation through CD28 in autoimmune disease development. This study provides important insights into the differential role of CD28 in naive and memory T cell responses and offers a new platform for design and interpretation of costimulatory based therapies.One-sentence summaryGenomic profiling of CD4 T cell activation reveals a sensitivity switch from TCR in naive to CD28 in memory cells.

scholarly journals Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

scholarly journals Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

2015 ◽  
Vol 89 (7) ◽  
pp. 3542-3556 ◽  
Author(s):  
Timothée Bruel ◽  
Chiraz Hamimi ◽  
Nathalie Dereuddre-Bosquet ◽  
Antonio Cosma ◽  
So Youn Shin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Responses ◽  
Cell Depletion ◽  
Viral Control ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Hiv 1

ABSTRACTThe spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8+T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8+T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8+T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8+T-cell responses. Among them, only one carried the protective MHC allele H6. After depletion, four of five controllers experienced a transient rebound of viremia. The return to undetectable viremia was accompanied by only modest expansion of SIV-specific CD8+T cells that lacked efficient SIV suppression capacityex vivo. In contrast, the depletion was associated with homeostatic activation/expansion of CD4+T cells that correlated with viral rebound. In one macaque, viremia remained undetectable despite efficient CD8+cell depletion and inducible SIV replication from its CD4+T cellsin vitro. Altogether, our results suggest that CD8+T cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control.IMPORTANCESpontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8+T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8+T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8+cells induced a rise in the viral load. However, viremia was correlated with CD4+T-cell activation subsequent to CD8+cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8+T cells. Our results suggest that CD8+T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.

scholarly journals Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression

2007 ◽  
Vol 204 (11) ◽  
pp. 2679-2692 ◽  
Author(s):  
Dennis J. Hartigan-O'Connor ◽  
Kristina Abel ◽  
Joseph M. McCune
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Compartment ◽  
Rapid Disease Progression ◽  
Cell Responses

The impact of regulatory T cells (T reg cells) on the course of HIV and SIV disease is unknown. T reg cells could suppress protective antiviral responses and accelerate disease progression. Alternatively, these cells might block T cell activation and thereby limit viral replication as well as activation-associated immunopathology. Given the higher frequency of T reg cells known to be present during human fetal ontogeny, such influences may be most important in the context of perinatal infection. We found that infant macaques had higher fractions of CD4+CD25+CD127lowFoxP3+ T reg cells in the peripheral blood and in lymphoid tissues, and that these T reg cells showed greater in vitro suppressive activity on a per cell basis. Infant and adult macaques were infected with SIVmac251 to test the influence of the T reg cell compartment on SIV-specific immune responses. After infection with SIV, most (three out of four) infant macaques had persistently high viral loads, weak and transient SIV-specific CD4+ and CD8+ T cell responses, and rapid disease progression. T reg cells in the infant but not in the adult directly suppressed SIV-specific CD4+ T cell responses, which were detectable only after depletion of T reg cells. In the case of both the infant and the adult macaque, T reg cells were not able to directly suppress SIV-specific CD8+ T cell responses and had no apparent effect on T cell activation. In aggregate, these observations suggest that the T reg cell compartment of the infant macaque facilitates rapid disease progression, at least in part by incapacitating SIV-specific CD4+ T cell responses.

scholarly journals A subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry.

2020 ◽  
Author(s):  
Alex Kayongo ◽  
Derrick Semugenze ◽  
Mary Nantongo ◽  
Fred Semitala ◽  
Anxious Jackson Niwaha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Viral Entry ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Controlled Study ◽  
Hiv 1

Abstract Background: World over, there are antiretroviral therapy naïve individuals infected with HIV who maintain their CD4+T cell count above 500 cells/µl over 7-10 years and viral loads well controlled below undetectable levels (termed elite controllers, ECs) or at least 2,000 copies/mL (termed viremic controllers, VCs) for at least 12 months. Mechanisms responsible for HIV control in these individuals have not been fully elucidated. We hypothesized that CD4+T cells from elite and viremic controllers are naturally resistant to HIV-1 infection by blocking R5-tropic viral entry. We conducted a case-controlled study in which archived peripheral blood from 31 ECs/VCs and 15 progressors were investigated using in vitro HIV-1 infectivity assays. Results: Briefly, we purified CD4+T cells from peripheral blood using EasySep CD4+ positive selection kit followed by CD4+T cell activation using IL-2, anti-CD28 and anti-CD3. Three days post-activation, CD4+T cells were spinoculated and co-cultured with vesicular stomatitis virus G (VSV-G)-pseudotyped HIV, R5 (ADA-enveloped)- and X4 (NL4.3-enveloped v)-tropic HIV-1. Three days post infection, we quantified and compared the percentage infection of CD4+T cells in cases and controls. We demonstrate that a subgroup of Ugandan elite and viremic controllers possess CD4+T cells that are specifically resistant to R5-tropic virus, remaining fully susceptible to X4-tropic virus. Conclusion: Our study suggests that a subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry. Further research is needed to explore mechanisms of HIV control in the African population.

scholarly journals 2406 The microbial-derived short-chain fatty acid butyrate directly and differentially inhibits gut T helper cell subset activation and proliferation

2018 ◽  
Vol 2 (S1) ◽  
pp. 31-32
Author(s):  
Jon Kibbie ◽  
Stephanie Dillon ◽  
Moriah Castleman ◽  
Jay Liu ◽  
Martin McCarter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
T Helper ◽  
T Helper Subsets ◽  
Hiv 1

OBJECTIVES/SPECIFIC AIMS: A hallmark of progressive HIV-1 infection is the massive activation and depletion of the gut barrier protective CD4 T helper subsets (Th17 and Th22) in the intestinal mucosa. The loss of these cells is thought to contribute to microbial translocation and systemic immune activation that occurs during chronic infection. In addition to the loss of protective Th subsets, we previously showed that chronically HIV-1 infected individuals have an altered colonic mucosal microbiome, which is in part characterized by a lower relative abundance of bacteria that produce the short-chain fatty acid butyrate in conjunction with increased relative abundance of gram-negative pathobionts. This dysbiosis was linked to markers of mucosal and systemic immune activation in these individuals. Following up on these clinical observations, we sought to understand how a loss of butyrate might contribute to HIV-associated inflammation. Initial studies showed that the addition of butyrate to cultured lamina propria mononuclear cells (LPMC) resulted in decreased pathobiont-driven gut T cell activation, HIV-1 infection levels and production of IL-17 and IFNy. Since the gut barrier protective Th17 and Th22 subsets are preferentially infected and depleted, which is critical to HIV-1 pathogenesis, we wanted to determine the mechanism by which butyrate modulates activation of these important Th subsets in the gut. METHODS/STUDY POPULATION: Total LPMCs or purified LP CD4 T cells were isolated from human jejunal tissue (n=3–6), labeled with CFSE and cultured with TCR/CD28 beads to mimic APC driven T cell activation, with the addition of butyrate at physiologic doses(0–2 mM). Four days after culture, secreted cytokine(IL-17 and IFNy) levels were measured by ELISA. Cells were then short-term (4 hr) mitogenically stimulated (PMA/Ionomycin) in the presence of a golgi transport inhibitor. Total CD4 T cell activation (CD38+/HLA-DR+, CD25+), proliferation (CFSElow), and frequencies of intracellular cytokines were measured by multi-color flow cytometry. Paired t-tests were performed to determine statistical significance. RESULTS/ANTICIPATED RESULTS: Butyrate inhibited LP CD4 T cell activation (p=0.013) and proliferation (p=0.015) within total LPMCs stimulated with TCR/CD28 beads in a dose-dependent manner, with significant activity starting at 0.125 mM. Quantification of total secreted cytokines revealed that butyrate significantly decreased both IL-17 and IFNy production after 4 days of culture at 0.0625 mM and 0.25 mM of butyrate, respectively. Assays using purified LP CD4 T cells demonstrated that butyrate directly decreased LP CD4 T cell activation, proliferation and cytokine production in response to TCR/CD28 stimulation. Studies on specific T helper subsets revealed that butyrate inhibited proliferation of Th17 cells at lower concentrations (IC50:0.147 mM) compared with Th1 (IC50:0.229 mM) and Th22 (IC50:0.258 mM) and Th non-IL-22/IL-17/IFNy producing (IC50:2.14 mM) subsets. In addition, it appeared there was a paradoxical increase of HIV-1 infection levels at lower concentrations of butyrate (0.125 mM). DISCUSSION/SIGNIFICANCE OF IMPACT: The addition of butyrate to activated LP CD4 T cells decreases TCR-mediated activation in a dose-dependent manner, and butyrate acts directly on purified LP CD4 T cell populations independent of other cell populations. Butyrate differentially inhibited the proliferation of Th17, Th1, and Th22 subsets, with Th17 cells being the most sensitive to butyrate but increased the infection levels of all T helper subsets at low concentrations. Further studies are needed to determine the mechanism of butyrate’s actions on LP Th cells and the sensitivity of Th17 cells to the inhibitory effects of butyrate. These results could help direct targeted manipulation of the colonic microbiome of HIV-1 infected individuals to help resolve inflammation and limit the impact of the infection in the gut mucosa and systemically.

scholarly journals Mesangial Cells Exhibit Features of Antigen-Presenting Cells and Activate CD4+ T Cell Responses

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hongyu Yu ◽  
Shaoyuan Cui ◽  
Yan Mei ◽  
Qinggang Li ◽  
Lingling Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mesangial Cells ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Antigen Presenting

Background. Mesangial cells play a prominent role in the development of inflammatory diseases and autoimmune disorders of the kidney. Mesangial cells perform the essential functions of helping to ensure that the glomerular structure is stable and regulating capillary flow, and activated mesangial cells acquire proinflammatory activities. We investigated whether activated mesangial cells display immune properties and control the development of T cell immunity. Methods. Flow cytometry analysis was used to study the expression of antigen-presenting cell surface markers and costimulatory molecules in mesangial cells. CD4+ T cell activation induced by mesangial cells was detected in terms of T cell proliferation and cytokine production. Results. IFN-γ-treated mesangial cells express membrane proteins involved in antigen presentation and T cell activation, including MHC-II, ICAM-1, CD40, and CD80. This finding suggests that activated mesangial cells can take up and present antigenic peptides to initiate CD4+ T cell responses and thus act as nonprofessional antigen-presenting cells. Polarization of naïve CD4+ T cells (Th0 cells) towards the Th1 phenotype was induced by coculture with activated mesangial cells, and the resulting Th1 cells showed increased mRNA and protein expression of inflammation-associated genes. Conclusion. Mesangial cells can present antigen and modulate CD4+ T lymphocyte proliferation and differentiation. Interactions between mesangial cells and T cells are essential for sustaining the inflammatory response in a variety of glomerulonephritides. Therefore, mesangial cells might participate in immune function in the kidney.

scholarly journals Role of Lymphotoxin α in T-Cell Responses during an Acute Viral Infection

2002 ◽  
Vol 76 (8) ◽  
pp. 3943-3951 ◽  
Author(s):  
M. Suresh ◽  
Gibson Lanier ◽  
Mary Katherine Large ◽  
Jason K. Whitmire ◽  
John D. Altman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Lymphotoxin Α

ABSTRACT The importance of lymphotoxin α (LTα) in lymphoid organogenesis is well established. Although LTα has been implicated in the pathogenesis of T-cell-mediated immunopathologies, the requirement for LTα in T-cell activation and effector function in vivo is not well understood. To determine the role of LTα in T-cell activation in vivo, we compared the generation of antigen-specific T-cell responses between wild type (+/+) and LTα-deficient (LTα−/−) mice during an acute infection with lymphocytic choriomeningitis virus (LCMV). Our studies showed that LCMV-infected LTα−/− mice had a profound impairment in the activation and expansion of virus-specific CD8 T cells in the spleen, as determined by cytotoxicity assays, intracellular staining for gamma interferon, and staining with major histocompatibility complex class I tetramers. Further, the nonlymphoid organs of LTα−/− mice also contained substantially lower number of LCMV-specific CD8 T cells than those of +/+ mice. Greatly reduced virus-specific CD8 T-cell responses in LTα−/− mice led to a defect in LCMV clearance from the tissues. In comparison to that in +/+ mice, the activation of LCMV-specific CD4 T cells was also significantly attenuated in LTα−/− mice. Adoptive transfer experiments were conducted to determine if abnormal lymphoid architecture in LTα−/− mice caused the impairment in the activation of LCMV-specific T-cell responses. Upon adoptive transfer into +/+ mice, the activation and expansion of LCMV-specific LTα−/− T cells were restored to levels comparable to those of +/+ T cells. In a reciprocal cell transfer experiment, activation of +/+ T cells was significantly reduced upon transfer into LTα−/− mice. These results showed that impairment in the activation of LCMV-specific T cells in LTα−/− mice may be due to abnormal lymphoid architecture and not to an intrinsic defect in LTα−/− T cells.

scholarly journals GTPase-activating protein Rasal1 associates with ZAP-70 of the TCR and negatively regulates T-cell tumor immunity

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Youg Raj Thaker ◽  
Monika Raab ◽  
Klaus Strebhardt ◽  
Christopher E. Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cd4 T Cell ◽  
Gtpase Activating Protein ◽  
Cell Responses

Abstract Immunotherapy involving checkpoint blockades of inhibitory co-receptors is effective in combating cancer. Despite this, the full range of mediators that inhibit T-cell activation and influence anti-tumor immunity is unclear. Here, we identify the GTPase-activating protein (GAP) Rasal1 as a novel TCR-ZAP-70 binding protein that negatively regulates T-cell activation and tumor immunity. Rasal1 inhibits via two pathways, the binding and inhibition of the kinase domain of ZAP-70, and GAP inhibition of the p21ras-ERK pathway. It is expressed in activated CD4 + and CD8 + T-cells, and inhibits CD4 + T-cell responses to antigenic peptides presented by dendritic cells as well as CD4 + T-cell responses to peptide antigens in vivo. Furthermore, siRNA reduction of Rasal1 expression in T-cells shrinks B16 melanoma and EL-4 lymphoma tumors, concurrent with an increase in CD8 + tumor-infiltrating T-cells expressing granzyme B and interferon γ-1. Our findings identify ZAP-70-associated Rasal1 as a new negative regulator of T-cell activation and tumor immunity.

scholarly journals Role of Lipids in Morphogenesis of T-Cell Microvilli

2021 ◽  
Vol 12 ◽  
Author(s):  
Marek Cebecauer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cortical Actin ◽  
Surface Receptors ◽  
Cell Responses ◽  
Cytoskeleton Reorganization ◽  
Membrane Protrusions

T cells communicate with the environment via surface receptors. Cooperation of surface receptors regulates T-cell responses to diverse stimuli. Recently, finger-like membrane protrusions, microvilli, have been demonstrated to play a role in the organization of receptors and, hence, T-cell activation. However, little is known about the morphogenesis of dynamic microvilli, especially in the cells of immune system. In this review, I focus on the potential role of lipids and lipid domains in morphogenesis of microvilli. Discussed is the option that clustering of sphingolipids with phosphoinositides at the plasma membrane results in dimpling (curved) domains. Such domains can attract phosphoinositide-binding proteins and stimulate actin cytoskeleton reorganization. This process triggers cortical actin opening and bundling of actin fibres to support the growing of microvilli. Critical regulators of microvilli morphogenesis in T cells are unknown. At the end, I suggest several candidates with a potential to organize proteins and lipids in these structures.

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