Antibody-dependent Responses Research Articles

The role of SAP and SLAM family molecules in the humoral immune response

Effective B cell-mediated immunity, including the formation of germinal centers and the generation of high-affinity memory B cells and long-lived plasma cells, is dependent on CD4(+) T cells. Immunodeficiencies that present with defects in the antibody response have provided insights into the molecular mechanisms of B cell responses and the provision of T cell help. One such immunodeficiency is X-linked lymphoproliferative disease (XLP), which results from mutations in SH2D1A, the gene encoding SLAM-associated protein (SAP). Patients with XLP present with humoral defects characterized by hypogammaglobulinemia. We now know that SAP, through its signaling downstream of multiple members of the signaling lymphocytic activation molecule (SLAM) family of cell surface receptors, plays a crucial role in many aspects of this immune response. Here, we discuss the role of SAP in the generation of humoral immunity, particularly T cell-dependent antibody responses and the generation of germinal centers.

IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T(FH)) cells. T(FH) cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T(FH) cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T(FH) cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T(FH) cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T(FH) cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.

Developmental Immunotoxicology Assessment of Rituximab in Cynomolgus Monkeys

Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy.

Intrinsic Properties of immunoglobulin IgG1 Isotype-Switched B Cell Receptors Promote Microclustering and the Initiation of Signaling

Memory B cells express high-affinity, immunoglobulin GB cell receptors (IgG BCRs) that enhance B cell responses, giving rise to the rapid production of high-affinity, IgG antibodies. Despite the central role of IgG BCRs in memory responses, the mechanisms by which the IgG BCRs function to enhance B cell responses are not fully understood. Using high-resolution live-cell imaging, we showed that IgG1 BCRs dramatically enhanced the earliest BCR-intrinsic events that followed within seconds of B cells' encounter with membrane bound antigen, including BCR oligomerization and BCR microcluster growth, leading to Syk kinase recruitment and calcium responses. The enhancement of these early events was dependent on a membrane proximal region of the IgG1 cytoplasmic tail not previously appreciated to play a role in IgG1 BCR signaling. Thus, intrinsic properties of the IgG1 BCR enhance early antigen-driven events that ultimately translate into heightened signaling.

Auto-reconstitution of the T-cell compartment by radioresistant hematopoietic cells following lethal irradiation and bone marrow transplantation

In lethally irradiated bone marrow chimeras, part of the reconstituted T-cell compartment is derived from the irradiated host, but the detailed origin and functional activity of host-derived T cells has not been thoroughly analyzed. Herein, we determine the origin and function of radioresistant host-derived T cells. Lethally irradiated thymectomized or nonthymectomized C57BL/6 host mice were reconstituted with syngeneic bone marrow, itself incapable of generating T cells. Using fetal thymic organ cultures, bulk and limiting dilution assays on OP9-DL1 stromal cells, unambiguous cohorts of thymus-derived and peripheral T-cell-derived T cells were phenotypically characterized by flow cytometry and functionally characterized by their ability to participate in a T-cell-dependent antibody response. Both thymus-derived and peripheral T-cell-derived host T cells are functional and can reconstitute 35% of the normal T-cell pool. By comparing thymectomized vs nonthymectomized hosts, host-derived T cells were shown to comprise a major (70%) subpopulation of de novo generated, thymus-derived, polyclonal, naïve cells, and a minor subpopulation of surviving, peripheral, oligoclonal, memory-like cells. Unlike euthymic recipients, mice whose T cells were derived from surviving peripheral T cells were frequently incapable of mounting a T-cell-dependent antibody response. Host-derived thymocytes regenerated in an interleukin-7-dependent fashion from conventional DN2 thymocytes and their differentiation recapitulated normal thymic ontogeny. We characterized, for the first time, functional radioresistant DN2-phenotype thymic T-cell precursors, the T-cell progeny of which might provide a first line of defense against infections during the lymphopenic phase post-bone marrow transplantation.

Antibody-mediated rejection: treatment alternatives and outcomes

Over the past 10 years, thanks to the development of sensitive methods of antibody detection and markers of antibody injury such as C4d staining, the role of anti-human leukocyte antigen (HLA) and non-HLA alloantibodies as effectors of acute and chronic immune allograft injury has been revisited. Antibody-mediated rejection (AMR) defines all allograft rejection caused by antibodies directed against donor-specific HLA molecules, blood group antigen (ABO)-isoagglutinins, or endothelial cell antigens. Antibody-mediated rejection can be a recalcitrant process, resistant to therapy and carries an ominous prognosis to the graft. In concordance with these views, treatment protocols for AMR use permutations of a multiple-prong approach that include (1) the suppression of the T-cell dependent antibody response, (2) the removal of donor reactive antibody, (3) the blockade of the residual alloantibody, and (4) the depletion of naive and memory B-cells. Although all published protocols report a variable rate of success, a major weakness of all current protocols is the lack of effective anti-plasma cell agents. In comparison to acute AMR, the treatment for chronic AMR (CAMR) is not well characterized. Although in acute AMR large titers of pre-existent alloantibodies result in massive activation of the complement system and lytic injury of the graft endothelium, thereby requiring aggressive and fast removal of the offending agents, in CAMR, complement activation results in sublytic endothelial cell injury and activation. Although this type of injury results in chronic graft failure, its slow progression likely renders it amenable of suppression by heightening of maintenance immunosuppression and anti-idiotypic blockade of the circulating alloantibody without the need of plasma exchange. In this review, we will discuss the rationale behind the design of treatment protocols for acute AMR and CAMR as well as their reported results and complications.

Induction of IgG3 to LPS via Toll-Like Receptor 4 Co-Stimulation

B-cells integrate antigen-specific signals transduced via the B-cell receptor (BCR) and antigen non-specific co-stimulatory signals provided by cytokines and CD40 ligation in order to produce IgG antibodies. Toll-like receptors (TLRs) also provide co-stimulation, but the requirement for TLRs to generate T-cell independent and T-cell dependent antigen specific antibody responses is debated. Little is known about the role of B-cell expressed TLRs in inducing antigen-specific antibodies to antigens that also activate TLR signaling. We found that mice lacking functional TLR4 or its adaptor molecule MyD88 harbored significantly less IgG3 natural antibodies to LPS, and required higher amounts of LPS to induce anti-LPS IgG3. In vitro, BCR and TLR4 signaling synergized, lowering the threshold for production of T-cell independent IgG3 and IL-10. Moreover, BCR and TLR4 directly associate through the transmembrane domain of TLR4. Thus, in vivo, BCR/TLR synergism could facilitate the induction of IgG3 antibodies against microbial antigens that engage both innate and adaptive B-cell receptors. Vaccines might exploit BCR/TLR synergism to rapidly induce antigen-specific antibodies before significant T-cell responses arise.

Antigen-specific human T-cell responses and T cell–dependent production of human antibodies in a humanized mouse model

AbstractHumanized mice with a functional human immune system would be very useful for in vivo studies of human immunobiology. We have previously shown that cotransplantation of human fetal thymus/liver tissues and CD34+ fetal liver cells into immunodeficient nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice leads to the development of multiple lineages of human lymphohematopoietic cells and formation of secondary lymphoid organs with normal architecture. Here, we evaluated the ability of these humanized mice to develop antigen-specific, T cell–dependent antibody responses after in vivo immunization with T-dependent antigen, 2,4-dinitrophenyl hapten-keyhole limpet hemocyanin (DNP23-KLH). Human T cells from DNP23-KLH–immunized mice showed strong proliferation in response to KLH in vitro. Furthermore, T cell–dependent production of DNP-specific human antibodies (mainly IgG1 and IgG2) was detected in all immunized mice. These results confirm that a functional human immune system can be established in immunodeficient mice through cotransplantation of human fetal thymus/liver tissues and CD34+ hematopoietic stem/progenitor cells.

Robust NK Cell-Mediated Human Immunodeficiency Virus (HIV)-Specific Antibody-Dependent Responses in HIV-Infected Subjects

Antibody-dependent cellular cytotoxicity (ADCC) is a potentially effective adaptive immune response to human immunodeficiency virus (HIV) infection. The study of ADCC responses has been hampered by the lack of simple methods to quantify these responses and map effective epitopes. We serendipitously observed that standard intracellular cytokine assays on fresh whole blood from a cohort of 26 HIV-infected subjects identified non-T lymphocytes expressing gamma interferon (IFN-gamma) in response to overlapping linear peptides spanning HIV-1 proteins. The effector cells were CD3(-) CD4(-) CD8(-) CD14(-) CD2(+) CD56(+/-) NK lymphocytes and degranulated granzyme B and perforin in response to antigen stimulation. Serum transfer assays demonstrated that the specific response was mediated by immunoglobulin G. Fresh blood samples from half of the HIV-infected cohort demonstrated robust HIV peptide-specific IFN-gamma expression by NK cells, predominately to Env, Pol, and Vpu HIV-1 proteins. Responses were readily mapped to define minimal epitopes utilizing this assay. Antibody-dependent, HIV-specific NK cell recognition, involving components of both innate and adaptive immune systems, represents a potentially effective immune response to induce by vaccination.

Determinants of maternal infection associated with virus infection of the fetus and newborn infant

Congenital infection with human cytomegalovirus (HCMV) is most common intrauterine acquired virus infection in infants in the developed world. Rates of congenital HCMV infection range from 0.2%-2.0% in live births. Although maternal infection with this virus rarely results in clinical symptoms, approximately 10% infants born with congenital HCMV infection can exhibit symptomatology ranging from mild hepatitis to severe multiorgan dysfunction, including damaging central nervous system infection. CNS infection can result in microcephaly, retinitis, and abnormalities in psychomotor function. More commonly, infants are clinically asymptomatic at birth but between 10-20% of infected infants will exhibit long term deficits in neurological function, with hearing loss being the most common long-term sequelae. Congenital HCMV infection is thought to be the most common non-familial cause of hearing loss. Although these characteristics of congenital HCMV infection are well described in studies from the developed world, little is known about the natural history of this infection in resource constrained countries. However, several studies have demonstrated that the incidence of congenital HCMV infection increases with increasing maternal infection. Recent findings from Brazil and India are consistent with these earlier studies and indicate that congenital HCMV infection occurs in 1-2% of newborn infants in most of the world's populations. Because HCMV infection is universal in these maternal populations and infection is acquired early in life, these findings indicate that maternal immunity to this virus is insufficient to prevent infection and perhaps can only modulate the incidence of disease in infected infants. Studies from the US have demonstrated that infected infants born to women with preconceptional immunity exhibit rates of developmental abnormalities similar to those infants born to women with primary infection acquired during pregnancy. The mechanisms that account for the inability of maternal immunity to prevent infection and limit disease in the developing fetus infected with HCMV have not been defined, but reinfection with new strains of virus has been shown to occur in normal host following community exposure. Reinfection of previously infected hosts with new strains of virus is common in animal models and recent studies in normal women suggest that rates of reinfection could exceed 20% per annum. HCMV has been shown to encode a number of viral functions that can evade both innate and adaptive immunity in-vitro and in experimental animal models. Although antiviral antibodies have been shown to neutralize virus in-vitro, strain dependent virus neutralizing antibody responses have been well described and appear to arise from minor sequence variation (1-3%) in some envelop glycoproteins such as gB whereas significant variations of > 25% have been reported in other envelop glycoproteins (gN). Whether these differences account for reinfection with different strains of HCMV and contribute to disease in congenitally infected infants remains to be determined. However, the apparent contribution of reinfection to the natural history of this congenital infection in the developing world suggests that HCMV could be a significant cause of morbidity in infants in resource-constrained countries as well as in the developed world. from Fourth Dominique Dormont International Conference. Host-Pathogen Interactions in Chronic Infections Paris, France. 13-15 December 2007

Interleukin-15 Increases Vaccine Efficacy through a Mechanism Linked to Dendritic Cell Maturation and Enhanced Antibody Titers

Interleukin-15 (IL-15) is generally considered to sustain T-cell memory and to be a growth factor for natural killer cells. Previous data from our laboratory demonstrated that IL-15 is also an important factor for developing human dendritic cells. For this study, we investigated the effects of IL-15 on antibody responses in mice to a recombinant staphylococcal enterotoxin B (SEB) vaccine (STEBVax) in a preclinical model of toxic shock syndrome induced by SEB. We observed that mouse spleen cells treated with IL-15 in ex vivo culture gained a dendritic cell-like phenotype. Administration of IL-15 to mice also resulted in an increased number of mature CD11c+ dendritic cells in mouse spleens. A significant, IL-15 dose-dependent increase in antigen-specific antibody was observed after coadministration with the vaccine and an aluminum-based adjuvant (alhydrogel). Furthermore, the coadministration of IL-15 with STEBVax and alhydrogel also protected mice from lethal toxic shock above the levels that obtained without IL-15. Thus, the vaccine response enhanced by IL-15 appears to be mediated by mature dendritic cells and results in prevalent seroconversion to Th2-dependent antibodies. This suggests a potential use of IL-15 as an adjuvant for antibody-dependent responses to vaccines.

Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner

CD40 ligand (CD40L) is an essential effector cytokine for macrophage activation, dendritic cell licensing, and T-cell-dependent antibody responses. Although CD40L is known to be made de novo following antigen recognition, several reports have described surface mobilization of preformed, intracellular CD40L in certain CD4(+) effector T cells. Here we show that rapid surface expression of preformed CD40L following antigen recognition is a general property of both effector and memory CD4(+) T cells, including in vitro and in vivo activated T-cell-receptor transgenic T cells, memory phenotype CD4(+) T cells from pathogen-free naive mice, and polyclonal virus-specific effector and memory T cells. Intracellular CD40L is stored in secretory lysosomes, and colocalizes more strongly with Fas ligand than with CTLA-4, two other molecules that are delivered to the cell surface following antigen recognition. Stimulated surface expression of preformed CD40L is found in memory CD4(+) T cells from CD40-deficient mice, indicating that it does not depend on CD40-induced internalization for delivery to the secretory compartment. We suggest that delivery of preformed CD40L to antigen-presenting cells (APCs) could enable antigen-specific activation of APCs in transient interactions that are too brief to permit de novo synthesis of CD40L.

Regulation of the Germinal Center Response by MicroRNA-155

MicroRNAs are small RNA species involved in biological control at multiple levels. Using genetic deletion and transgenic approaches, we show that the evolutionarily conserved microRNA-155 (miR-155) has an important role in the mammalian immune system, specifically in regulating T helper cell differentiation and the germinal center reaction to produce an optimal T cell-dependent antibody response. miR-155 exerts this control, at least in part, by regulating cytokine production. These results also suggest that individual microRNAs can exert critical control over mammalian differentiation processes in vivo.

T cell tolerance to AChR, the autoantigen in myasthenia gravis, is mediated primarily by peripheral mechanisms (128.25)

Abstract In myasthenia gravis (MG), a T-cell dependent antibody response is directed against acetylcholine receptor (AChR) at the neuromuscular junction. To study T cell tolerance, we generated a transgenic mouse in which the TAChRα chain is expressed as a self protein. This transgenic was bred to nude mice and thymus transplants were performed to produce progeny expressing TAChRα in the thymus and/or the periphery (muscle). These mice were immunized with the TAChRα dominant epitope, p146–162, and in vitro proliferation of responding T cells was measured. Since AChR is expressed at low levels in the thymus, it was presumed that central tolerance would be important. However, this was not the case; only mice with peripheral expression of TAChRα showed tolerance (a lack of proliferation). Furthermore, CFSE-labeled TAChR specific T cells from a TCR transgenic were adoptively transferred into TAChR transgenic (tolerizing) and non-transgenic recipients. Following immunization, proliferation of the transferred T cells was lower in the TAChR transgenic host. Moreover, when the TAChR transgene was bred to scurfy mice, progeny lacking Tregs (foxp3−/Y) exhibited an increase in serum anti-TAChR Ig. Autoantibodies were not seen in the foxp3+/Y mice or in mice lacking Aire function (which have defective central tolerance). These results are consistent with a primary role for peripheral tolerance in regulating the response to AChR. Supported by an APC Subcontract, a UTHSCSA ERC grant and NIH (T32AG021890, T32DE11438).

Interleukin-15 increases vaccine efficacy through a mechanism linked to dendritic cell maturation and enhanced antibody titers (47.16)

Abstract Interleukin-15 (IL-15) is generally considered to be a growth factor for NK cells and for sustaining T-cell memory. However, previous data from our laboratory demonstrated that IL-15 is an important factor for development of human dendritic cells. In this study, we investigated the effect of IL-15 on antibody responses to STEBVax, a recombinant staphylococcal enterotoxin B (SEB) vaccine, in a pre-clinical model of toxic-shock syndrome induced by SEB. We first observed IL-15 treated mouse spleen cells in culture gained a dendritic cell-like morphology compared to untreated controls. Further, administration of IL-15 to mice resulted in an increased number of CD11c+dendritic cells recovered from spleens. A significant, IL-15 dose-dependent increase in antigen-specific antibody was observed after co-administration with vaccine. This effect required including an aluminum-based adjuvant (Alhydrogel). The co-administration of STEBVax with IL-15 and Alhydrogel also resulted in a significant increase in protection of mice from lethal toxic shock above levels obtained without IL-15. Thus, the antibody response enhanced by IL-15 appears to be mediated by mature dendritic cells. This suggests a potential use of IL-15 as an adjuvant for antibody-dependent responses to vaccines

The effect of ranitidine on antibody responses to polysaccharide vaccines in patients with B‐cell chronic lymphocytic leukaemia

To analyse the effects of ranitidine treatment on vaccination induced antibody responses in patients with chronic lymphocytic leukaemia (CLL). Fifty CLL patients were vaccinated with tetanus conjugated Hib vaccine and a 23-valent pneumococcal polysaccharide vaccine with (n = 25) or without (n = 25) ranitidine treatment in a matched case--control setting. Anti tetanus toxoid (TT), anti-Hib and anti-pneumococcal antibody levels were determined before and after vaccination. Additionally, cytokine levels were assessed in patients treated with ranitidine. Vaccination-induced increases in anti-Hib and anti-TT antibody levels were higher in the ranitidine group compared with the control group. Anti-pneumococcal antibody responses were not improved by administration of ranitidine. Higher levels of IL-18 were found in patients treated with ranitidine compared with healthy controls. Levels of IL-6, IL-8, IL-18, RANTES, IP-10, sVCAM-1 and sICAM-1 were within normal ranges and did not change during ranitidine treatment. Ranitidine treatment improves vaccination-induced T-cell dependent antibody responses in patients with CLL but has no beneficial effect on the response to vaccination with unconjugated polysaccharide antigens.

Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell–dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell–independent responses, fitting with the robustness and high affinity of T cell–dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell–directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency.

Primary Immune Response to Sheep Red Blood Cells (SRBC) as the Conventional T-Cell Dependent Antibody Response (TDAR) Test

The production of antigen-specific antibodies represents a major defense mechanism of humoral immune responses. Several assays have been developed to assess T-cell-dependent antibody responses (TDAR). Of these assays, the antibody forming cell assay (AFC) or plaque forming cell (PFC) assay and ELISA are the two most often used tests to assess immunotoxicity. Historically, the T-cell-dependent antigen of choice has been sheep red blood cells (SRBC). The SRBC AFC assay is considered the “gold standard” for TDAR based on extensive intra- and inter-laboratory validation in mice and has been utilized for over 35 years. The quantification of the primary AFC response (i.e., the specific IgM antibody-forming cell response) was found to provide one of the best predictors of immunotoxicity in mice. The SRBC-specific ELISA is relatively new, with the first publication of the method appearing in 1993. Data from the application of using both the SRBC specific AFC and ELISA for evaluation of potential immunotoxicity of chemicals in rodents and the pros and cons and associated issues of each method were presented. Specifically, the following was discussed: (1) studies investigating the incorporation of the SRBC-specific IgM ELISA in rats on standard toxicology study; (2) characterization of an approach to developmental immunotoxicology assessment in the rat using SRBC as the antigen; and, (3) data from an inter-laboratory study comparing the AFC assay and ELISA in outbred rodents using both cyclophosphamide and dexamethasone.

Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity

TFE3 and TFEB are broadly expressed transcription factors related to the transcription factor Mitf. Although they have been linked to cytokine signaling pathways in nonlymphoid cells, their function in T cells is unknown. TFE3-deficient mice are phenotypically normal, whereas TFEB deficiency causes early embryonic death. We now show that combined inactivation of TFE3 and TFEB in T cells resulted in a hyper-immunoglobulin M syndrome due to impaired expression of CD40 ligand by CD4(+) T cells. Native TFE3 and TFEB bound to multiple cognate sites in the promoter of the gene encoding CD40 ligand (Cd40lg), and maximum Cd40lg promoter activity and gene expression required TFE3 or TFEB. Thus, TFE3 and TFEB are direct, physiological and mutually redundant activators of Cd40lg expression in activated CD4(+) T cells critical for T cell-dependent antibody responses.

Dissecting CXCR5+ T cell populations – on the quest for a better understanding of B cell help during T dependent antibody responses

High affinity antibody responses against protein antigens critically depend on T cell help during the germinal center reaction. So called follicular helper T cells (T(FH)), present in the germinal centers of human tonsils, have been characterised by the expression of CXCR5; however, only subgroups of the heterogeneous CXCR5 T cell population strongly support antibody production. A paper in this issue of the European Journal of Immunology demonstrates that high expression of the inducible co-stimulator (ICOS) molecule, rather than CD57, correlates with the follicular helper function. This result represents another step towards a better understanding of the complexity of the different T cell subpopulations participating in the germinal center reaction.