Influenza viruses are T cell-independent B cell mitogens.

UV-inactivated influenza virus A strains of subtypes H1, H2, H3, and H6 were shown to be mitogenic for unprimed splenic lymphocytes from BALB/c mice. Representative viruses of these four subtypes all behaved as T cell-independent B cell mitogens. The magnitude of the proliferative response was determined by the subtype of the hemagglutinin molecule: H2 and H6 viruses were the most potent mitogens, and H3 viruses were moderately mitogenic, whereas H1 viruses induced only low, but significant, levels of proliferation. Mitogenesis was inhibited by antiviral sera and by monoclonal antibodies directed against hemagglutinin.     

Rap1b regulates B cell development, homing, and T cell-dependent humoral immunity

Rap1 is a small GTPase that belongs to Ras superfamily. This ubiquitously expressed GTPase is a key regulator of integrin functions. Rap1 exists in two isoforms: Rap1a and Rap1b. Although Rap1 has been extensively studied, its isoform-specific functions in B cells have not been elucidated. In this study, using gene knockout mice, we show that Rap1b is the dominant isoform in B cells. Lack of Rap1b significantly reduced the absolute number of B220(+)IgM(-) pro/pre-B cells and B220(+)IgM(+) immature B cells in bone marrow. In vitro culture of bone marrow-derived Rap1b(-/-) pro/pre-B cells with IL-7 showed similar proliferation levels but reduced adhesion to stromal cell line compared with wild type. Rap1b(-/-) mice displayed reduced splenic marginal zone (MZ) B cells, and increased newly forming B cells, whereas the number of follicular B cells was normal. Functionally, Rap1b(-/-) mice showed reduced T-dependent but normal T-independent humoral responses. B cells from Rap1b(-/-) mice showed reduced migration to SDF-1, CXCL13 and in vivo homing to lymph nodes. MZ B cells showed reduced sphingosine-1-phosphate-induced migration and adhesion to ICAM-1. However, absence of Rap1b did not affect splenic B cell proliferation, BCR-mediated activation of Erk1/2, p38 MAPKs, and AKT. Thus, Rap1b is crucial for early B cell development, MZ B cell homeostasis and T-dependent humoral immunity.     

Discrimination of suppressor T cells of humoral and cell-mediated immunity by anti-Ly and anti-Ia sera.

Evidence is presented which demonstrates that the T lymphocytes which suppress humoral and cell-mediated immunity in CBA/H mice differ in the cell surface structures they express. The suppressor T cells of delayed-type hypersensitivity are Ly-1⁺, Ly-2^? and Ia^?, whereas the suppressor T cells of antibody formation are Ly-1^?, Ly-2⁺ and Ia⁺.     

The humoral immunity against diphtheria

Results of the conducted study showed that naturally acquired antibacterial and postvaccinal antitoxic antibodies against diphtheria were found in human blood sera. Challenge of ADT-M toxoid to adults resulted in production of antitoxic as well as antibacterial antibodies in high concentrations. In response to challenge of ADT-M toxoid simultaneously with bacterial vaccine against diphtheria Codivac both antibacterial and antitoxic antibodies were synthesized in blood on optimal physiologic levels. This study revealed dynamics of some specific characteristics of humoral immune response after challenge of two different vaccines against diphtheria--ADT-M toxoid and Codivac vaccine.     

Genetic controls of T cell-independent Thy-1 alloantibody responses

Early and late primary IgM antibody responses of mice to Thy-1.1 antigens showed different antigenic and cellular requirements. We studied genetic controls of the early primary responses, which could be induced by subcellular thymocyte antigens independently of host T-cell activity. All Thy-1.2 mouse strains of Igh ^a(BALB/c and BC8), Igh-V ^aC^b(BAB14), Igh ^d(AKR/Cum), Igh ^j(CBA/J, C3H/HeN, C3H.SW, and C3H.JK), and Igh ⁿ(NZB) definitely responded early to Thy-1.1 antigens from AKR/J (Igh ^d), A.Thy-1.1 (Igh ^e), or B10.Thy-1.1 (Igh ^b) mice or SD rats, whereas all strains of Igh ^b(C57BL/6, C57BL/10, B10.D2, B10.BR, B10.A, CB20 and CWB), Igh ^c(DBA/2), Igh ^e(A/J), and Igh ^o(C.AL20) responded poorly to the same antigens. This contrasts with the observation that both strains of Igh ^j(C3H/HeN) and Igh ^b(B10.BR) responded well at later times. As was the case for late responses, the matching of H-2 between donor and recipient resulted in early responses of exceptional quality in high-responder strains. It was concluded that under the influence of H-2, whose incompatibility between donor and recipient partially interferes with responses, early but not late primary Thy-1.1-specific antibody responses are selectively controlled by Igh-V or closely linked Ir gene(s) as a new V _Hmarker.Abbreviations used in this paper Tl T cell-independent - TD T cell-dependent - PFC plaque-forming cell(s) - Igh immunoglobulin heavy chain - V _H variable region of heavy chain - C _H constant region of heavy chain     

A T cell-independent mechanism of macrophage activation by interferon-gamma

A primary interest in immunity to intracellular pathogenic microorganisms and tumors is to understand the mechanisms by which macrophages are activated for various functions. Two parameters of macrophage activation are the expression of the class II histocompatibility proteins or Ia molecules (1), and cytotoxic activity. The ability of T cells to induce these responses has been extensively documented and occurs via their secretion of interferon-gamma (IFN-gamma) after interaction with antigen (2-6). However, in a recent study using mice with the severe combined immunodeficiency (scid) mutation (7) which have no detectable T or B cell functions (7-9), we were surprised to find the induction of Ia expression on macrophages and the partial inhibition of bacterial growth after infection with Listeria monocytogenes (10). We have now utilized neutralizing monoclonal antibodies specific for murine IFN-gamma to investigate the mechanism of macrophage activation in scid mice. We show here that IFN-gamma can be produced by scid mice in the absence of lymphocyte-mediated immunity, and this IFN-gamma is important for macrophage activation during infection with Listeria. These results indicate the presence of an important T lymphocyte-independent mechanism of macrophage activation and IFN-gamma production in response to infection.     

Playing with cellular and humoral immunity

An interesting and easy game for the teaching of immunology was developed by the authors. Previously distributed figure cards are used by students that have to ask questions of each other. Most students considered the game to be interesting (97.7%) and declared that it helped them to understand the subject. The authors emphasise the importance of improving the quality of teaching using visual memory, fun and competition.     

Ineffective humoral immunity in the elderly

As individuals age, dysfunction of the immune system leads to an increased incidence of infectious disease. Due to the complex network of cellular interactions and the multi-factorial process of aging, numerous impairments in humoral immunity have been reported. Advances in technology have allowed scientists to begin to identify the molecular mechanisms behind the age-associated decline.     

Cutting edge: an NK cell-independent role for Slamf4 in controlling humoral autoimmunity

Several genes within a syntenic region of human and mouse chromosome 1 are associated with predisposition to systemic lupus erythematosus. Analyses of lupus-prone congenic mice have pointed to an important role for the signaling lymphocyte activation molecule family (slamf)6 surface receptor in lupus pathogenesis. In this article, we demonstrate that a second member of the Slamf gene family, Slamf4 (Cd244), contributes to lupus-related autoimmunity. B6.Slamf4(-/-) mice spontaneously develop activated CD4 T cells and B cells and increased numbers of T follicular helper cells and a proportion develop autoantibodies to nuclear Ags. B6.Slamf4(-/-) mice also exhibit markedly increased autoantibody production in the B6.C-H-2bm12/KhEg → B6 transfer model of lupus. Although slamf4 function is best characterized in NK cells, the enhanced humoral autoimmunity of B6.Slamf4(-/-) mice is NK cell independent, as judged by depletion studies. Taken together, our findings reveal that slamf4 has an NK cell-independent negative regulatory role in the pathogenesis of lupus a normally non-autoimmune prone genetic background.     

T cell-independent, TLR-induced IL-12p70 production in primary human monocytes

IL-12p70 is a key cytokine for the induction of Th1 immune responses. IL-12p70 production in myeloid cells is thought to be strictly controlled by T cell help. In this work we demonstrate that primary human monocytes can produce IL-12p70 in the absence of T cell help. We show that human monocytes express TLR4 and TLR8 but lack TLR3 and TLR7 even after preincubation with type I IFN. Simultaneous stimulation of TLR4 and TLR8 induced IL-12p70 in primary human monocytes. IL-12p70 production in peripheral blood myeloid dendritic cells required combined stimulation of TLR7/8 ligands together with TLR4 or with TLR3 ligands. In the presence of T cell-derived IL-4, but not IFN-gamma, stimulation with TLR7/8 ligands was sufficient to stimulate IL-12p70 production. In monocytes, type I IFN was required but not sufficient to costimulate IL-12p70 induction by TLR8 ligation. Furthermore, TLR8 ligation inhibited LPS-induced IL-10 in monocytes, and LPS alone gained the ability to stimulate IL-12p70 in monocytes when the IL-10 receptor was blocked. Together, these results demonstrate that monocytes are licensed to synthesize IL-12p70 through type I IFN provided via the Toll/IL-1R domain-containing adaptor inducing IFN-beta pathway and the inhibition of IL-10, both provided by combined stimulation with TLR4 and TLR8 ligands, triggering a potent Th1 response before T cell help is established.     

Differential effects of concanavalin A and phytohemagglutinin on murine immunity. Suppression and enhancement of humoral immunity.

The abilities of concanavalin A (Con A) and phytohemagglutinin P (PHA) to selectively induce different T-cell activities affecting humoral immunity were evaluated. The mitogens were intravenously injected before, with, or after injection of sheep red blood cells (SRBC) into mice, and the 3 to 6-day plaque-forming cell (PFC) responses were assessed. Mitogenic treatment differentially influenced the resultant in vivo PFC responses to SRBC. The in vivo suppressive effects induced by Con A were shown to be temporary; only the Day 4 PFC response was inhibited. Con A given 3 hr before, with, or after the antigenic challenge enhanced the PFC response. In contrast, PHA given at all intervals inhibited both the 4- and 5-day PFC response. Neither mitogen appeared to affect the kinetics of the in vivo PFC response to SRBC. Both mitogens enhanced in vivo DNA synthesis by the splenic cells, and Con A appeared biphasic in its stimulation. Con A-induced effects on the humoral immune response were short-lived and transient, while PHA induced a longer-lasting effect on humoral immunity.     

Polydnavirus-mediated suppression of insect immunity

Polydnaviruses are symbiotic proviruses of some ichneumonid and braconid wasps that modify the physiology, growth and development of host lepidopteran larvae. Polydnavirus infection targets neuroendocrine and immune systems, altering behavior, stunting growth, and immobilizing immune responses to wasp eggs and larvae. Polydnavirus-mediated disruption of cellular and humoral immunity renders parasitized lepidopteran larvae suitable for development of wasp larvae as well as more susceptible to opportunistic infections. Evidence from the Campoletis sonorensis polydnavirus system indicates that the unique genomic organization of polydnaviruses may have evolved to amplify the synthesis of immunosuppressive viral proteins. Immunosuppressive viruses have been essential to elucidating vertebrate immunity. Polydnaviruses have similar potential to clarify insect immune responses and may also provide novel insights into the role of insect immunity in shaping polydnavirus genomes.