scholarly journals Requirement for CD4+ T Cells in the Friend Murine Retrovirus Neutralizing Antibody Response: Evidence for Functional T Cells in Genetic Low-Recovery Mice

1998 ◽  
Vol 72 (11) ◽  
pp. 9400-9403 ◽  
Author(s):  
Heidi J. Super ◽  
Diane Brooks ◽  
Kim Hasenkrug ◽  
Bruce Chesebro
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Response ◽  
T Helper Cells ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Immunoglobulin M ◽  
T Helper ◽  
Helper Cells ◽  
Fv Antibody

ABSTRACT Recovery from infection with the Friend murine leukemia retrovirus complex (FV) requires T-helper cells and cytotoxic T cells as well as neutralizing antibodies. Several host genes, including genes of the major histocompatibility complex (H-2) and anH-2-unlinked gene, Rfv-3, influence these FV-specific immune responses. (B10.A × A/Wy)F1mice, which have the H-2a/aRfv-3r/s genotype, fail to mount a detectable FV-specific T-cell proliferative response but nevertheless produce FV-specific neutralizing immunoglobulin M (IgM) antibodies and can eliminate FV viremia. Thus, this IgM response, primarily influenced by the Rfv-3 gene, may be T-cell independent. To test this idea, mice were depleted of either CD4+ or CD8+ T-cell populations in vivo and were monitored for the effect on the neutralizing antibody response following FV infection. Surprisingly, mice in which CD4+ cells were depleted showed undetectable FV-neutralizing antibody responses and high viremia levels compared to nondepleted or CD8-depleted animals. In addition to knocking out the FV antibody response, CD4+ T-cell depletion reduced survival time significantly, further indicating the importance of CD4+ T cells. These studies revealed the first evidence for a functional T-cell response following FV infection in these low-recovery mice and showed that CD4+ T-helper cells are required for the Rfv-3-controlled FV antibody response.

scholarly journals Neonatal lymphocyte subpopulations analysis and maternal preterm premature rupture of membranes: a pilot study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Margherita Amadi ◽  
Silvia Visentin ◽  
Francesca Tosato ◽  
Paola Fogar ◽  
Giulia Giacomini ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Helper Cells ◽  
Lymphocyte Subpopulations ◽  
T Helper ◽  
Premature Rupture Of Membranes ◽  
Premature Rupture ◽  
Preterm Premature Rupture ◽  
Helper Cells

Abstract Objectives Preterm premature rupture of membranes (pPROM) causes preterm delivery, and increases maternal T-cell response against the fetus. Fetal inflammatory response prompts maturation of the newborn’s immunocompetent cells, and could be associated with unfavorable neonatal outcome. The aims were to examine the effects of pPROM (Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstet Gynecol Clin N Am 2005;32:411) on the newborn’s and mother’s immune system and (Test G, Levy A, Wiznitzer A, Mazor M, Holcberg G, Zlotnik A, et al. Factors affecting the latency period in patients with preterm premature rupture of membranes (pPROM). Arch Gynecol Obstet 2011;283:707–10) to assess the predictive value of immune system changes in neonatal morbidity. Methods Mother-newborn pairs (18 mothers and 23 newborns) who experienced pPROM and controls (11 mothers and 14 newborns), were enrolled. Maternal and neonatal whole blood samples underwent flow cytometry to measure lymphocyte subpopulations. Results pPROM-newborns had fewer naïve CD4 T-cells, and more memory CD4 T-cells than control newborns. The effect was the same for increasing pPROM latency times before delivery. Gestational age and birth weight influenced maturation of the newborns’ lymphocyte subpopulations and white blood cells, notably cytotoxic T-cells, regulatory T-cells, T-helper cells (absolute count), and CD4/CD8 ratio. Among morbidities, fewer naïve CD8 T-cells were found in bronchopulmonary dysplasia (BPD) (p=0.0009), and more T-helper cells in early onset sepsis (p=0.04). Conclusions pPROM prompts maturation of the newborn’s T-cell immune system secondary to antigenic stimulation, which correlates with pPROM latency. Maternal immunity to inflammatory conditions is associated with a decrease in non-major histocompatibility complex (MHC)-restricted cytotoxic cells.

scholarly journals Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses

2021 ◽  
Vol 6 (55) ◽  
pp. eabb6852
Author(s):  
Young Min Son ◽  
In Su Cheon ◽  
Yue Wu ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Helper Cells ◽  
Critical Role ◽  
Cell Formation ◽  
Influenza Virus Infection ◽  
T Helper ◽  
Helper Cells ◽  
Cell Immunity

Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21–dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.

scholarly journals Tissue-resident CD4+ T helper cells assist protective respiratory mucosal B and CD8+ T cell memory responses

2020 ◽  
Author(s):  
Young Min Son ◽  
In Su Cheon ◽  
Yue Wu ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Cell Formation ◽  
Influenza Virus Infection ◽  
T Helper ◽  
Helper Cells ◽  
Mucosal Tissues ◽  
Cell Immunity ◽  
Cd8 T Cell Memory

AbstractThe roles of CD4+ T helper cells (TH) in shaping localized memory B and CD8+ T cell immunity in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local assistance for the optimal development of tissue-resident memory B (BRM) and CD8+ T (TRM) cells following the resolution of primary influenza virus infection. We identify a population of tissue-resident CD4+ TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell features and mediate local help of CD4+ T cells to B and CD8+ T cells. Optimal TRH cell formation requires lung B cells and transcription factors involved in TFH or TRM development. Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population that is specialized in assisting the development of mucosal protective B and CD8+ T cell responses in situ.

scholarly journals Ripk3 Signaling Restricts the Development of Peripheral T Cell Lymphoma in Tet2 Deficient Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3318-3318
Author(s):  
Kanak Joshi ◽  
Ryan Mack ◽  
Lei Zhang ◽  
Shanhui Liu ◽  
Mark Sellin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Helper Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Wild Type ◽  
T Helper ◽  
Peripheral T Cell Lymphoma ◽  
Helper Cells

Abstract Inactive mutations of the Ten-eleven translocation (TET2) gene are commonly found in humans with multiple hematological malignancies including myeloproliferative neoplasm (MPN), acute myeloid leukemia, diffuse large B cell lymphoma, and peripheral T cell lymphomas (PTCL), and are frequently associated with poor prognosis and worse overall survival. TET2 mutations often occur in hematopoietic stem and progenitor cells (HSPCs) and are known to collaborate with additional mutations for full-blown malignant transformation. However, the molecular mechanism by which the disease identity is determined remains to be elucidated. Increased inflammatory cytokines are commonly detected in patients with TET2 mutations, which is associated with an increased risk of atherosclerotic cardiovascular diseases. Most Tet2 knockout (Tet2 -/-) mice develop MPN-like disease within 18 months, with only a few cases developing chronic lymphocyte leukemia-like disease at two years of age. The intestinal bacteria-induced inflammatory signaling plays a critical role in the pathogenesis of MPN-like disease in Tet2 -/- mice. Receptor-interacting protein kinase 3 (Ripk3) is a key mediator of inflammation cytokine-induced necroptosis and metabolic signaling. Compared to bone marrow (BM) cells isolated from wild-type mice, higher levels of Ripk3 activity can be detected in Tet2 -/- BM cells. To study the role of Ripk3 in Tet2 mutations associated with hematopoietic diseases, we crossed Tet2 conditional knockout (Tet2fx/fx Mx1-Cre +) mice with Ripk3 -/- mice to generate Tet2 and Ripk3 compound knockout (Tet2 -/-Ripk3 -/-) mice. Tet2 -/-Ripk3 -/- mice developed aggressive tumors by 12-15 months of age as characterized by profound hepatosplenomegaly and lymphadenopathy, with substantial lymphocytosis, neutrophilia, anemia, and thrombocytopenia. Histopathological analysis revealed an aggressive infiltration of tumor cells in the liver and spleen, and effacement of splenic follicular structures in diseased Tet2 -/-Ripk3 -/- mice. To characterize the type of malignancies, single-cell suspensions of the BM, peripheral blood (PB), and spleen from Tet2 -/-Ripk3 -/- were analyzed by flow cytometry and compared with wild-type and Tet2 -/- mice. As expected Tet2 -/- mice exhibited increased frequencies of myeloid cells in the PB, BM, and spleen. However, there was a marked expansion of CD4 + T cells in the PB, BM, and spleen of Tet2 -/-Ripk3 -/- mice. Detailed analyses of the T subsets demonstrated a marked expansion of both CD4 +PD1 +CXCR5 + follicular T helper cells (T fh) and CD4 +PD1 + peripheral T helper cells (T ph), indicating the development of a peripheral T cell lymphoma (PTCL) in the Tet2 -/-Ripk3 -/- mice. Additionally, disease characteristics including the reduced surface expression of CD3 in the tumor cells, increased levels of classical T h cytokines in the serum, as well as the presence of heterogeneous populations of cells within the tumor tissues recapitulate the pathological features of angioimmunoblastic T cell lymphoma (AITL), a subtype of PTCL. Elevated frequencies of splenic T fh and T ph cells were detected as early as 7 months of age in Tet2 -/-Ripk3 -/- mice. Such cells expressed inducible T cell costimulatory receptor (ICOS), an essential signaling mediator of the T fh development and proliferation. However, all other hematopoietic parameters including BM HSPCs and mature CD4 + T cells were comparable to wild type and single-gene Tet2 -/- mice. These results indicate that Ripk3 signaling inhibits PTCL development in Tet2 -/- mice by limiting the expansion of T fh and T ph cells. We are currently determining whether Ripk3 plays such a role by inducing necroptosis and/or restricting the differentiation of CD4 + naive T cells into peripheral T fh and T ph populations. We are also investigating whether Ripk3 signaling is inactivated in the tumor cells of human PTCL patients and whether we can treat such aggressive fatal diseases by reactivating Ripk3 signaling. Disclosures No relevant conflicts of interest to declare.

scholarly journals Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages.

1985 ◽  
Vol 162 (1) ◽  
pp. 117-127 ◽  
Author(s):  
W A Jefferies ◽  
J R Green ◽  
A F Williams
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
T Helper Cells ◽  
Peritoneal Macrophages ◽  
T Helper ◽  
Helper Cells

The rat W3/25 antigen that appears to be equivalent to human CD4 (T4) antigen is expressed on thymocytes and T helper cells and plays a role in the response of T helper cells to antigen. The W3/25 and anti-T4 antibodies also label macrophages. In this paper we examine whether the macrophage antigen is the same as that on T cells. New monoclonal antibodies against the rat CD4 antigen, MRC OX-35 through OX-38, are described, all of which label peritoneal macrophages from normal and athymic rats. The molecular weight of W3/25 antigen on macrophages is indistinguishable from that on T cells. We conclude that macrophages express authentic CD4 (W3/25) antigen. Another new monoclonal antibody, MRC OX-34, labels an antigen of 50-54,000 mol wt that is expressed on rat T but not B cells or peritoneal macrophages. It was used to control for the presence of any T cell products in immunoprecipitation from rat macrophage extracts.

Vaccine-Induced, Pseudorabies Virus-Specific, Extrathymic CD4+CD8+ Memory T-Helper Cells in Swine

1998 ◽  
Vol 72 (6) ◽  
pp. 4866-4873 ◽  
Author(s):  
Bertram T. Ober ◽  
Artur Summerfield ◽  
Christina Mattlinger ◽  
Karl-Heinz Wiesmüller ◽  
Günther Jung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
T Helper Cells ◽  
Pseudorabies Virus ◽  
Class Ii ◽  
T Cell Epitopes ◽  
T Helper ◽  
Helper Cells

ABSTRACT Pseudorabies virus (PRV; suid herpesvirus 1) infection causes heavy economic losses in the pig industry. Therefore, vaccination with live attenuated viruses is practiced in many countries. This vaccination was demonstrated to induce extrathymic virus-specific memory CD4+CD8+ T lymphocytes. Due to their major histocompatibility complex (MHC) class II-restricted proliferation, it is generally believed that these T lymphocytes function as memory T-helper cells. To directly prove this hypothesis, 15-amino-acid, overlapping peptides of the viral glycoprotein gC were used for screening in proliferation assays with peripheral blood mononuclear cells of vaccinated d/d haplotype inbred pigs. In these experiments, two naturally processed T-cell epitopes (T1 and T2) which are MHC class II restricted were identified. It was shown that extrathymic CD4+CD8+ T cells are the T-lymphocyte subpopulation that responds to epitope T2. In addition, we were able to show that cytokine secretion can be induced in these T cells through recall with inactivated PRV and demonstrated that activated PRV-primed CD4+CD8+ T cells are able to induce PRV-specific immunoglobulin synthesis by PRV-primed, resting B cells. Taken together, these results demonstrate that the glycoprotein gC takes part in the priming of humoral anti-PRV memory responses. The experiments identified the first T-cell epitopes so far known to induce the generation of virus-specific CD4+CD8+ memory T lymphocytes and showed that CD4+CD8+ T cells are memory T-helper cells. Therefore, this study describes the generation of virus-specific CD4+CD8+ T cells, which is observed during vaccination, as a part of the potent humoral anti-PRV memory response induced by the vaccine.

Renewal of the T-cell compartment in multiple sclerosis patients treated with glatiramer acetate

2009 ◽  
Vol 16 (2) ◽  
pp. 218-227 ◽  
Author(s):  
M. Chiarini ◽  
A. Sottini ◽  
C. Ghidini ◽  
C. Zanotti ◽  
F. Serana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Glatiramer Acetate ◽  
T Helper Cells ◽  
T Cell Repertoire ◽  
T Helper ◽  
Cell Repertoire ◽  
Helper Cells ◽  
Cell Diversity ◽  
Multiple Sclerosis Patients

The immunomodulating activity of glatiramer acetate on T-cells of multiple sclerosis patients has only been partially clarified. The objective of this work was to investigate whether glatiramer acetate modifies thymic release of newly produced T-cells and the peripheral composition of the T-cell repertoire. T-cell receptor excision circles, thymic naive (CD4+CD45RA+CCR7 +CD31+) T helper cells, and central (CD4+CD45RA -CCR7+) and effector (CD4+CD45RA-CCR7 -) memory T-cells were evaluated in 89 untreated patients, 84 patients treated for at least 1 year, and 31 patients beginning treatment at the time of inclusion in the study and then followed-up for 12 months; controls were 81 healthy donors. The T-cell repertoire was analysed in selected samples. The percentage of thymicnaive T helper cells was diminished in untreated patients, but rose to control values in treated subjects; a decrease in central memory T-cells was also observed in treated patients. Follow-up patients could be divided into two subgroups, one showing unmodified thymicnaive T helper cells and T-cell diversity, the other in which the increased release of new T-cells was accompanied by modifications of the T-cell repertoire. Glatiramer acetate modifies the peripheral T-cell pool by activating a thymopoietic pathway of T-cell release that leads to a different setting of T-cell diversity and, likely, to a dilution of autoreactive T-cells.

scholarly journals CD4+ T helper cells use CD154–CD40 interactions to counteract T reg cell–mediated suppression of CD8+ T cell responses to influenza

2013 ◽  
Vol 210 (8) ◽  
pp. 1591-1601 ◽  
Author(s):  
André Ballesteros-Tato ◽  
Beatriz León ◽  
Frances E. Lund ◽  
Troy D. Randall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
T Helper ◽  
Cell Responses

CD4+ T cells promote CD8+ T cell priming by licensing dendritic cells (DCs) via CD40–CD154 interactions. However, the initial requirement for CD40 signaling may be replaced by the direct activation of DCs by pathogen-derived signals. Nevertheless, CD40–CD154 interactions are often required for optimal CD8+ T cell responses to pathogens for unknown reasons. Here we show that CD40 signaling is required to prevent the premature contraction of the influenza-specific CD8+ T cell response. CD40 is required on DCs but not on B cells or T cells, whereas CD154 is required on CD4+ T cells but not CD8+ T cells, NKT cells, or DCs. Paradoxically, even though CD154-expressing CD4+ T cells are required for robust CD8+ T cell responses, primary CD8+ T cell responses are apparently normal in the absence of CD4+ T cells. We resolved this paradox by showing that the interaction of CD40-bearing DCs with CD154-expressing CD4+ T cells precludes regulatory T cell (T reg cell)–mediated suppression and prevents premature contraction of the influenza-specific CD8+ T cell response. Thus, CD4+ T helper cells are not required for robust CD8+ T cell responses to influenza when T reg cells are absent.

Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 1924-1931 ◽  
Author(s):  
Svenja Hardtke ◽  
Lars Ohl ◽  
Reinhold Förster
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Cell Area ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells ◽  
Cell Follicle

Abstract The production of high-affinity antibodies to T-dependent antigens requires the interaction of B cells and T helper cells expressing receptors specific for the same antigen. Although several mechanisms have been elucidated that regulate B-cell trafficking within lymphoid organs, less is known about molecular cues that guide the small subpopulation of CD4+ follicular T helper cells to B-cell follicles. Using adoptive transfer of transgenic T cells in mice, we demonstrate that antigen-induced activation leads to a finely tuned positioning of T cells either to the T-cell area or the B-cell follicle. We show that expression of CXCR5 is indispensable for T cells to enter B-cell follicles, whereas expression of CCR7 provides a counteracting signal to retain activated T cells in the T-cell area. Although only few T cells transiently migrate from the T-cell area to the B-cell follicle of peripheral lymph nodes following antigenic challenge, this step is essential to provide the help B cells require to produce antibodies efficiently. Thus, we demonstrate that the balanced expression of CCR7 and CXCR5 determines the positioning and proper function of follicular T helper cells.

scholarly journals Expansion of T Helper Cell Subsets in Chronic Lymphocytic Leukemia Cell Co-Cultures with Nurselike Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1746-1746
Author(s):  
Alicia Vaca ◽  
Mariela Sivina ◽  
Karen Clise-Dwyer ◽  
Ekaterina Kim ◽  
Michael J Keating ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Research Funding ◽  
T Helper Cell ◽  
T Cell Subsets ◽  
Helper Cell ◽  
T Helper ◽  
Helper Cells ◽  
Cell Counts

Background: In secondary lymphatic organs (SLO), chronic lymphocytic leukemia (CLL) cells form characteristic pseudo-follicles, also called proliferation centers, in which proliferating CLL cells are in intimate contact with CD4+ T helper cells. Despite evidence for a co-evolution of CLL cells and counterpart T helper cells, the prevalence and dynamics of T cell subsets, such as T follicular helper cells (TFH), T regulatory helper cells (TRegs) and IL-17-producing T helper cells (Th17) has not been characterized in detail. The CLL nurselike cell (NLC) model recapitulates key cellular and molecular interactions between CLL cells and the microenvironment in SLO, based on functional and gene expression studies, and represents a valid in vitro model for the SLO microenvironment in CLL. To gain insight into the potential role of T cells in CLL SLO, we utilized the NLC model to characterize T helper cell subsets and their dynamics in NLC co-cultures. Methods and Results: First, we quantified CD4+ and CD8+ T cell subsets in fresh peripheral blood mononuclear cell (PBMC) samples from 14 patients and then placed 1x107 PBMCs/ml in culture to establish NLC. We rechecked the relative proportion of CD4+ and CD8+ T cells, as well as absolute T cell counts, and their viability after 3, 6, 9, 12 and 14 days in NLC co-culture conditions. Interestingly, throughout the 14 days of culture, the number of T helper cells remained stable when compared to baseline samples. Next, we characterized T helper cell subsets in 25 different CLL samples, comparing CD4+ T cell subsets in freshly isolated CLL PBMC with matched samples harvested after 14 days of NLC culture. Samples were stained with subset-specific fluorescence-labeled antibody combinations, and analyzed by flow cytometry. NLC co-culture resulted in a significant expansion of TFH and TReg cells. TFH absolute cell counts assessed by flow cytometry using counting beads, increased from 9.4±2.2/μl at baseline to 29.0±5.9/μl in NLC co-cultures (n=14, p=0.001) and TReg from 17.0±3.3/μl to 51.0±15.0/μl (n=14, p=0.027). In contrast, Th17 absolute cell counts declined after 14 days of culture from 113.0±21.0/μl to 68.0±13.0/μl (n=14, p=0.001). Moreover, TH2 cells declined from 42.0±7.4/μl to 30.0±8.2/μl (n=14, p=0.005). Next, we analyzed for changes in TFH subsets (TFH1, TFH2 and TFH17). When compared to TFH cells from CLL PBMC, NLC culture resulted in a relative increase in TFH2 from 17.0±2.4% to 26.0±1.7% (n=25, p=0.013), and in TFH17 from 12.0±1.6% to 21.0±2.7% (n=25, p=0.006) In contrast, TFH1 frequency decreased after 14 days of culture (54.0±3.5% versus 34.0±2.9%, n=25, p=0.001). T follicular regulatory (TFr) cells also increase under co-culture conditions from undetectable to 4.8±1.9% (n=25, p=0.025)(Figure1). Looking at the maturity of CD4+ cells we noted a relative increase of central memory cells from 42.0±3.2% to 50.0±3.2% (n=25, p=0.023), whereas effector memory cells decreased from 34.0±3.4% to 26.0±2.7% (n=25, p=0.009), the fraction of naïve CD4+ cells remained unchanged. Next, we assessed the activation status of co-inhibitory receptors on CD3+CD4+ cells. We found a significant relative increase in CD4+ T cells expressing PD1 and CTLA-4 after 14 days of culture. Additionally, the TFH and TReg subsets demonstrated a significantly higher CTLA-4 expression after culture while TReg cells also addressed an increase in PD1 frequency. Furthermore, we observed a significantly higher CD28 expression on TFH and TReg subsets after 14 days of co-culture. Following, to address the residence and migration capacity of T cells in NLC co-cultures, we analyzed the CD69 and CD62L expression. Our results revealed significantly higher expression of CD69 in NLC co-cultures, whereas CD62L levels remained unchanged. Conclusion: The expansion of TFH and TReg cells in NLC co-cultures suggests the selection and clonal expansion of T cells that may support and engage in crosstalk with CLL cells. Additionally, the expansion of TFr and TFH17 cells could reflect a milieu of immune tolerance establishing in NLC co-cultures. Ongoing TCR sequencing of serial CD4+ T cell samples (baseline versus 14 days under NLC conditions) will characterize changes of clonal architecture in the T helper cell compartment, and will further improve our understanding of co-evolution of CLL and T helper cells. Disclosures Wierda: Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding. Burger:Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Pharmacyclics, an AbbVie company: Research Funding.

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