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Accessory molecule interactions can be critical in determining the outcome of a T cell's encounter with antigen. Cell adhesion proteins may augment T cell responses by facilitating TCR engagement of the antigen-MHC complex, while co-stimulatory molecules may deliver distinct signals that modulate T cell responsiveness. CD43 (leukosialin, sialophorin) has been suggested to influence cell activation by steric hindrance based upon the large size and glycosylation of the protein, as well as the relative abundance of the protein on the cell surface. In this paper we examine both in vitro and in vivo T cell-dependent responses in CD43-deficient mice. We demonstrate that T cells from CD43-deficient mice are hyper-responsive following both in vivo and in vitro activation, and that this is observed in response to not only TCR-CD3-mediated stimulation, but also following receptor-independent activation. This data suggests that mechanisms other than non-specific steric hindrance are important in the regulation of T cell activation by CD43. [ABSTRACT FROM PUBLISHER]

Purpose: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need., Methods: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia., Results: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively., Conclusion: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3-4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.Clinical Trial Registration: ClinicalTrials.gov, NCT01853748., (© 2022. The Author(s).)

Purpose: The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC)., Methods: Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1., Results: The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH., Conclusion: Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH., Competing Interests: Sara TolaneyConsulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Sanofi, Celldex, Bristol Myers Squibb, Paxman, Seattle Genetics, Odonate Therapeutics, AbbVie, Silverback Therapeutics, G1 Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Immunomedics/Gilead, Mersana, CertaraResearch Funding: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Immunomedics, Odonate Therapeutics, Sanofi, Seattle GeneticsTravel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, Celldex Chau DangHonoraria: Puma Biotechnology, eviCore healthcareConsulting or Advisory Role: Puma Biotechnology, eviCore healthcareResearch Funding: Genentech/Roche, Puma Biotechnology Denise YardleyConsulting or Advisory Role: Novartis, Biotheranostics, Bristol Myers Squibb, G1 Therapeutics, Athenex, Immunomedics, Sanofi/Aventis, R-Pharm, LillySpeakers' Bureau: Novartis, Genentech/Roche, Genentech/RocheResearch Funding: Genentech/Roche, Novartis, MedImmune, Lilly, Medivation, Pfizer, Tesaro, Macrogenics, AbbVie, Merck, Clovis Oncology, Amgen, Biomarin, Biothera, Dana Farber Cancer Hospital, Incyte, Innocrin Pharma, Nektar, NSABP Foundation, Odonate Therapeutics, PolyphorTravel, Accommodations, Expenses: Novartis, Genentech/Roche Steven IsakoffConsulting or Advisory Role: AbbVie, OncoPep, Puma Biotechnology, Seattle Genetics, NovartisResearch Funding: Genentech, PharmaMar, AbbVie, OncoPep, Merck, AstraZeneca/MedImmune, Outcomes4Me Vicente ValeroHonoraria: Genentech/Roche, Merck, NovartisConsulting or Advisory Role: Genentech/Roche, Novartis, MerckTravel, Accommodations, Expenses: Genentech/Roche Therese MulveyConsulting or Advisory Role: Outcomes4Me Ron BoseConsulting or Advisory Role: GenentechResearch Funding: Puma Biotechnology Antonio WolffConsulting or Advisory Role: Ionis PharmaceuticalsResearch Funding: Biomarin, CelldexPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications related to methylation in breast cancer and has assigned his rights to JHU and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Katherine Reeder-HayesResearch Funding: Pfizer Hope RugoHonoraria: Puma Biotechnology, MylanConsulting or Advisory Role: SamsungResearch Funding: Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, Merck, Immunomedics, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, Sermonix Pharmaceuticals, AstraZenecaTravel, Accommodations, Expenses: Pfizer, Novartis, Macrogenics, Mylan, Daiichi Sankyo, AstraZeneca Spain, MerckOpen Payments Link: https://openpaymentsdata.cms.gov/summary Bhuvaneswari RamaswamyConsulting or Advisory Role: Eisai Lowell HartHonoraria: Novartis, Daiichi Sankyo, AstraZeneca, Seattle Genetics, G1 Therapeutics, Veracyte, Karyopharm TherapeuticsConsulting or Advisory Role: Genentech/Roche, Amgen, G1 Therapeutics, Merck, Seattle GeneticsSpeakers' Bureau: Bristol Myers Squibb, Lilly, Pfizer, Genentech, AstraZeneca, NovartisResearch Funding: Novartis, Genentech/Roche, Bristol Myers Squibb, G1 Therapeutics, Seattle Genetics Vijayakrishna GadiLeadership: SEngine Precision MedicineStock and Other Ownership Interests: Sengine precision medicine, Novilla, 3rdEyeBio, New Equilibrium BiosciencesConsulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Novartis, SanofiSpeakers' Bureau: Seagen, bioTheranosticsResearch Funding: Genentech/Roche, SignalOne Bio, AgendiaTravel, Accommodations, Expenses: NovartisOpen Payments Link: https://openpaymentsdata.cms.gov/physician/2511 Bryan SchneiderHonoraria: Lilly, Research to Practice Paul MarcomConsulting or Advisory Role: Genentech/Roche, ImmunomedicsResearch Funding: Novartis, Genentech/Roche, AstraZeneca, Verily, Glycomimetics, MillenniumOpen Payments Link: https://openpaymentsdata.cms.gov/physician/237508/summary Kathy AlbainConsulting or Advisory Role: Novartis, Pfizer, Myriad Genetics, Genomic Health, Agendia, Genentech/RocheResearch Funding: Seattle GeneticsOther Relationship: Puma Biotechnology Nadine TungResearch Funding: AstraZeneca Rita NandaConsulting or Advisory Role: Merck, Genentech/Roche, Pfizer, Macrogenics, Daiichi Sankyo, Athenex, Aduro Biotech, ION Pharma, Seattle Genetics, ImmunomedicsResearch Funding: Corcept Therapeutics, Celgene, Merck, Seattle Genetics, Genentech/Roche, Odonate Therapeutics, Pfizer, AstraZeneca, AbbVie, ImmunomedicsOther Relationship: G1 Therapeutics Rachel JankowitzHonoraria: EisaiConsulting or Advisory Role: Merck Mothaffar RimawiConsulting or Advisory Role: Macrogenics, Daiichi Sankyo, Seattle Genetics, GenentechResearch Funding: Pfizer Vandana AbramsonEmployment: HCA HealthcareConsulting or Advisory Role: Eisai, Daiichi Sankyo, AbbvieResearch Funding: Genentech/Roche, Lilly Paula PohlmannLeadership: Immunonet BioSciencesStock and Other Ownership Interests: Immunonet BioSciencesHonoraria: Dava Oncology, OncLive/MJH Life Sciences, Frontiers—PublisherConsulting or Advisory Role: Personalized Cancer Therapy, OncoPlex Diagnostics, Immunonet BioSciences, Pfizer, HERON, Puma Biotechnology, Sirtex Medical, Caris Life Sciences, Juniper Pharmaceuticals, Bolt BiotherapeuticsSpeakers' Bureau: Genentech/RocheResearch Funding: Genentech/Roche, Fabre-Kramer, Advanced Cancer Therapeutics, Caris Centers of Excellence, Pfizer, Pieris Pharmaceuticals, Cascadian Therapeutics, Bolt Biotherapeutics, Byondis, SeagenPatents, Royalties, Other Intellectual Property: United States Patent no. 8486413, United States Patent no. 8501417, United States Patent no. 9023362, United States Patent no. 9745377, Patent application Catherine Van PoznakResearch Funding: BayerPatents, Royalties, Other Intellectual Property: UpToDate Andres Forero-TorresEmployment: Seattle GeneticsStock and Other Ownership Interests: Seattle Genetics Minetta LiuResearch Funding: Eisai, Seattle Genetics, Novartis, Roche/Genentech, GRAIL, Merck, Tesaro, Menarini Silicon Biosystems, Genomic HealthTravel, Accommodations, Expenses: GRAIL, Merck, Menarini Silicon Biosystems, Pfizer, Genomic Health, AstraZeneca, Ionis Pharmaceuticals Kathryn RuddyPatents, Royalties, Other Intellectual Property: My husband is a co-inventor of technology licensed by Mayo Clinic to AliveCor (MountainView, CA), which makes a smartphone-enabled remote ECG monitoring system Richard GelberResearch Funding: AstraZeneca, Novartis, Roche, Merck, PfizerTravel, Accommodations, Expenses: Roche, AstraZeneca, Novartis Bill BarryEmployment: Rho Ann PartridgePatents, Royalties, Other Intellectual Property: I receive small royalty payments for co-authoring the breast cancer survivorship section of UpToDateTravel, Accommodations, Expenses: Novartis Eric WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: GenentechOther Relationship: InfiniteMD Ian KropEmployment: AMAG Pharmaceuticals, Freeline TherapeuticsLeadership: AMAG Pharmaceuticals, Freeline TherapeuticsStock and Other Ownership Interests: AMAG Pharmaceuticals, Freeline Therapeutics, VertexHonoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, Ionis Pharmaceuticals, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech, PfizerNo other potential conflicts of interest were reported.

Introduction: Single agent chemotherapy is standard for second and third line treatment of non-small cell lung cancer (NSCLC). Combination therapy to date has not proven to be superior to single agents in this setting, often adding toxicity without any additional efficacy. We investigated the activity and tolerability of the combination of oxaliplatin, pemetrexed, and bevacizumab in patients with previously treated advanced NSCLC., Methods: This multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (500 mg/m), oxaliplatin (120 mg/m), and bevacizumab (15 mg/kg), given every 21 days, in patients with previously treated advanced NSCLC. Eligibility criteria included performance status 0 to 1, nonsquamous histology, and at least one prior chemotherapy regimen. Patients with treated brain metastases were allowed. The primary end point was response rate, with secondary endpoints of progression-free survival and overall survival., Results: Thirty-six patients were enrolled on this study. Treatment was well tolerated; the most common grade 3 toxicity was hypertension, which was easily managed with oral medications. The nine (25%) patients with treated brain metastases had no episodes of cerebral hemorrhage. Of the 34 patients evaluable for tumor response, none had complete response, nine (27%) had partial response, 15 (44%) had stable disease, and 10 (29%) had progressive disease. Median progression-free survival was 5.8 months (95% confidence interval 4.1-7.8 months) and median overall survival was 12.5 months (95% confidence interval 7.3-17 months)., Conclusions: Treatment with oxaliplatin and pemetrexed in combination with the targeted antiangiogenic agent bevacizumab yielded promising efficacy with manageable toxicity in the previously treated advanced NSCLC population.

Galectin-1 kills immature thymocytes and activated peripheral T cells by binding to glycans on T cell glycoproteins including CD7, CD45, and CD43. Although roles for CD7 and CD45 in regulating galectin-1-induced death have been described, the requirement for CD43 remains unknown. We describe a novel role for CD43 in galectin-1-induced death, and the effects of O-glycan modification on galectin-1 binding to CD43. Loss of CD43 expression reduced galectin-1 death of murine thymocytes and human T lymphoblastoid cells, indicating that CD43 is required for maximal T cell susceptibility to galectin-1. CD43, which is heavily O-glycosylated, contributes a significant fraction of galectin-1 binding sites on T cells, as T cells lacking CD43 bound approximately 50% less galectin-1 than T cells expressing CD43. Although core 2 modification of O-glycans on other glycoprotein receptors is critical for galectin-1-induced cross-linking and T cell death, galectin-1 bound to CD43 fusion proteins modified with either unbranched core 1 or branched core 2 O-glycans and expression of core 2 O-glycans did not enhance galectin-1 binding to CD43 on T cells. Moreover, galectin-1 binding clustered CD43 modified with either core 1 or core 2 O-glycans on the T cell surface. Thus, CD43 bearing either core 1 or core 2 O-glycans can positively regulate T cell susceptibility to galectin-1, identifying a novel function for CD43 in controlling cell death. In addition, these studies demonstrate that different T cell glycoproteins on the same cell have distinct requirements for glycan modifications that allow recognition and cross-linking by galectin-1.

We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein of leukocytes, in the binding of mycobacteria to host cells. CD43-transfected HeLa cells bound Mycobacterium avium, but not Salmonella typhimurium or Shigella flexneri. Quantitative bacteriology showed that macrophages (M(phi)) from wild-type mice (CD43(+/+)) bound M. avium, Mycobacterium bovis (bacillus Calmette-Guérin), and Mycobacterium tuberculosis (strain H37Rv), whereas M(phi) from CD43 knockout mice (CD43(-/)-) did not. Fluorescence microscopy demonstrated that the associated M. avium had been ingested by the CD43(+/+) M(phi). The inability of CD43(-/)- M(phi) to bind M. avium could be restored by addition of galactoglycoprotein (Galgp), the extracellular mucin portion of CD43. The effect of Galgp is not due to opsonization of the bacteria, but required its interaction with the M(phi) other mucins had no effect. CD43 expression by the M(phi) was also required for optimal induction by M. avium of tumor necrosis factor (TNF)-alpha production, which likewise could be reconstituted by Galgp. In contrast, interleukin (IL)-10 production by M. avium-infected M(phi) was CD43 independent, demonstrating discordant regulation of TNF-alpha and IL-10. These findings describe a novel role of CD43 in promoting stable interaction of mycobacteria with receptors on the M(phi) enabling the cells to respond specifically with TNF-alpha production.

The mAb 1B11 has been characterized as recognizing the activation-associated glycoform of murine CD43, a heavily O-glycosylated protein implicated in leukocyte homing. When hemopoietic cells from CD43-/- mice were stained with 1B11, CD43-independent binding of 1B11 was observed on peripheral CD8 T cells and at low levels on thymocytes, while no binding was detected on CD4 T cells, B cells, or bone marrow cells. Levels of 1B11 staining were comparable in lymph node CD8+ T cells from both CD43-/- mice and CD43+/+ mice. We sought to identify the CD43-independent target of 1B11 expressed on CD8 T cells. Previous work had demonstrated that neuraminidase treatment of lymph node cells (LNC) enhanced 1B11 binding on CD43+/+ LNC; this enhancement was also observed in CD43-/- LNC. We show that neuraminidase-enhanced 1B11 binding in CD43-/- LNC and EL4 thymoma cells is CD43 independent and that 1B11 detects a novel target of apparent mass of approximately 200 kDa identified as a hyposialylated form of CD45RB preferentially expressed on peripheral CD8, but not CD4, T cells. Our data also show that the recognition of CD43 and CD45RB by 1B11 is differentially affected by O-linked glycosylation and sialic acid. Whereas 1B11 recognition of CD43 on activated T cells required both core 2 O-glycan branching and sialic acid, 1B11 recognition of CD45 only occurred in the absence of both core 2 glycosylation and sialic acid.

CD43, a large highly glycosylated molecule, is arguably the most abundant molecule on the surface of T cells. Nevertheless, the function of CD43 remains unclear. Utilizing fluorescence microscopy, we find that CD43 is excluded from the T cell-APC contact site. This exclusion is Ag dependent since optimal CD43 exclusion requires Ag-pulsed APC, and since signaling through CD3, in the absence of any other receptor ligand interactions, can induce the modulation of CD43. These data suggest that CD43 may function as a barrier to nonspecific T cell-APC interactions that is removed as a result of T cell activation. Exclusion from the interaction site is a unique feature of CD43 and not universally found for all large highly glycosylated molecules since CD45 is not excluded. Thus, CD43 may represent a novel regulatory molecule on the T cell surface that can direct T cell interactions by changing its location on the cell surface.

We report that the cell surface mucin CD43 acts as an anti-adhesin on T lymphocytes. CD43-deficient murine lymphocytes homed significantly more frequently to secondary lymphoid organs than wild-type cells. Intravital microscopy of peripheral lymph node venules revealed that CD43-deficient lymphocytes were twice as likely to tether, roll, and stick than wild-type cells. This effect was due to CD43 interference with the homing receptor, L-selectin, and was most pronounced in venules with low L-selectin ligand density. In vitro, CD43-deficient cells tethered to L-selectin ligands more efficiently and rolled more slowly than wild-type lymphocytes. Thus, CD43 exerts a negative regulatory effect on T cell trafficking by counterbalancing L-selectin-mediated adhesion.

Background & Aims: The cholecystokinin (CCK)-B/gastrin receptor is one of several regulators of gastric acid secretion and mucosal growth. To elucidate the contribution of this receptor relative to other trophic and secretory factors, mice that lack the CCK-B/gastrin receptor have been generated and studied., Methods: Both alleles of the CCK-B/gastrin receptor were inactivated by targeted gene disruption. Analysis of the mice included measurement of basal gastric pH and plasma gastrin levels. In addition, multiple gastric mucosal cell types were identified by immunostaining and quantified., Results: Homozygous mutant mice were viable, fertile, and appeared grossly normal into adulthood. The receptor-deficient mice exhibited a marked increase in basal gastric pH (from 3.2 to 5.2) and an approximately 10-fold elevation in plasma gastrin concentration compared with wild-type controls. In the stomach of mutant animals, parietal and enterochromaffin-like cells were decreased, providing a likely explanation for the reduction in acid output. In the antrum, a decrease in somatostatin cell density and an increase in the gastrin cell number were observed, consistent with the concomitant elevation in circulating gastrin., Conclusions: Together, these findings demonstrate the importance of the CCK-B/gastrin receptor in maintaining the normal cellular composition and function of the gastric mucosa.

CD43 is a cell-surface sialoglycoprotein expressed by a variety of haematopoietically derived cells, including T lymphocytes. Earlier observations of defective CD43 expression by T lymphocytes from boys with the X-chromosome-linked Wiskott-Aldrich syndrome suggested the importance of CD43 in lymphocyte function. Subsequent studies have suggested that CD43 facilitates leukocyte adhesion and has a co-stimulatory role during T-cell activation. To define the physiologically relevant function(s) of CD43, we have generated CD43-knockout mice. We report here that CD43-deficient T cells from such mice show a marked increase in their in vitro proliferative response to concanavalin A, anti-CD3, the superantigen SEB and allostimulation. Additionally, CD43-deficient T cells show a substantial enhancement in homotypic adhesion and in their ability to bind different ligands, including fibronectin and the intercellular adhesion molecule ICAM-1. Vaccinia-virus-infected CD43-knockout mice mounted an augmented anti-vaccinia cytotoxic T-cell response compared with their wild-type littermates, yet developed an increased virus load. We conclude that CD43 negatively regulates T-cell activation and adhesion and is important for viral clearance.

CD43 is a cell surface sialoglycoprotein expressed by most cells of hematopoietic origin, including all T lymphocytes. Elimination of CD43 expression by gene targeting in the CEM T cell line results in its increased homotypic adhesion and binding to HIV-1 gp120. Here we report that the CD43-negative CEM cells show increased susceptibility to HIV-1 infection and increased viral replication compared with the parental CD43+ CEM cell line. Increased HIV-1 replication also was observed in CEM cells with diminished CD43 expression secondary to functional inactivation of a single CD43 allele. The CD43- CEM cells were more susceptible to HIV-1-induced cytopathicity than their CD43+ counterparts. HIV-1 replication also was increased in the CD43- CEM cells after transfection with the infectious HIV molecular clone pNL4-3. These data suggest that factors that diminish CD43 expression on T lymphocytes may enhance their susceptibility to HIV-1 infection.

T lymphocytes bound to autologous immunoglobulin (surface Ig + T cells) and serum antibodies that bind to allogeneic lymphocytes have been detected in HIV-1-infected individuals, but their significance in the immunopathogenesis of HIV-1 infection is uncertain. We tested peripheral blood from HIV-1-infected individuals to determine if surface Ig+ T cells are specific for HIV-1 infection and are associated with CD4+ lymphocyte depletion. The majority of HIV-1-infected individuals contained substantial numbers of circulating surface Ig+ T cells. The presence of such cells was restricted to seropositive individuals and not related to risk factors associated with the acquisition of HIV-1 infection. Autologous immunoglobulin was detected on both CD4+ and CD8+ cells in all patients tested. Most individuals with surface Ig+ T lymphocytes also had serum anti-T-lymphocyte antibodies. The presence of surface Ig+ T lymphocytes correlated significantly with lower absolute CD4+ lymphocyte counts only in asymptomatic, HIV-1-infected individuals.

Antisera to peptides that represent regions within the fourth and fifth conserved domains of the human immunodeficiency virus type 1 (HIV-1) gp120 were tested for recognition of the gp120 glycoprotein and for the ability to interfere with gp120 binding to the CD4 receptor molecule. Antisera to both peptides contained equivalent antibody titers, showed equivalent reactions with denatured gp120 on Western blot, and had group-specific reactivity. Preincubation of gp120 with either anti-peptide sera prebound to a solid phase substantially blocked soluble CD4 binding to gp120. Similarly, preincubation of gp120 with CD4-positive cells substantially diminished recognition of gp120 by both anti-peptide antisera. These results provide serologic evidence that regions near or within the fourth and fifth conserved domains of gp120 are involved in CD4 binding. However, neither anti-peptide sera could block soluble gp120 from binding to CD4-positive cells nor inhibited HIV-1 envelope-mediated syncytium formation or virus infection. These results demonstrate that antisera to regions proximal to the CD4 binding site of gp120 may compete poorly with CD4 for gp120 binding.

A small population of normal thymic lymphocytes, like the majority of thymic leukemia cells, formed cellular complexes with thymic epithelium-like stromal cells in pseudoemperipolesis. The properties of the complex-forming cells in preleukemic AKR thymus were analyzed after separation of the cells into subpopulations on the basis of cell size and surface antigen expression by using a fluorescence-activated cell sorter. Complex-forming ability was associated with large cells and the following phenotypes: high Thy-1.1, low brain associated theta antigen, high H-2Kk, high Lyt-1, high gp70 and Ia negativity. These properties coincide in general with those of blast cells in the subcapsular zone of the thymus, which have been shown to consist mostly of complex-forming cells. The possible significance of complex formation of normal and leukemic thymocytes with thymic stromal cells is discussed.