Requirement for three signals in "T-independent" (lipopolysaccharide-induced) as well as in T-dependent B cell responses.

Abstract

It has recently been reported (1-3) that at least three different activation signals are required by resting B lymphocytes to generate clones of antibody-secreting cells during a T helper cell (Tn)Ldependent humoral immune response: one signal is generated when B cells "see" antigen, another one when the TH recognize major histocompatibility complex (MHC) (I region) determinants on the B cell. These two early signals are apparently required to render the B cell responsive to a third signal provided by T cell-derived nonspecific helper factor(s) for B cell responses (BHF). Thus, TH provide two different types of B cell activation signals, one MHC-carrierspecific and one nonspecific (1-6). But it is still not clear whether an antigen (hapten)-B cell interaction generates by itself an activation signal or serves only to focus haptenlinked carrier determinants (and thus T help) onto the B cell (4, 7). In addition, it is not clear at the present time whether different factors (interleukins) are involved in B cell proliferation vs. differentiation (8-15) and whether the MHC-carrier-specific Tnsignal can be mediated by soluble T cell products (16-18). There is still conflicting evidence concerning the capacity of combinations of interleukins, e.g., concanavalin A (Con A) supernatants or secondary mixed leukocyte culture supernatants (MLC SN), to entirely substitute for Tn in T cell-depleted B cell cultures (8-15, 19, 20).If there is a requirement for at [east three signals in Tn-dependent B cell responses, one may also have to reconsider the hypothesis that a mitogen such as bacterial lipopolysaccharide (LPS) can bypass all three signals and by itself induce a full B cell response (3,21). Different authors have to some extent observed synergistic effects between LPS and antigen (22, 23) or T help (24, 25) or both (26) but not a strict requirement for three signals. A major problem in the study of B cell activation, in particular concerning the role of LPS or the capacity of BHF to act as T-replacing factor, resides in the fact that B cell populations used for such studies still contain T cells that can themselves provide signals, especially in high density cultures.

B cell dependence on and response to accessory signals in murine lupus strains.

“…In fact, it has been shown that in low density cultures, even in the presence of LPS, three signals are required to induce an anti-SRBC PFC response (21).…”

“…Similarly, B cells do not proliferate in response to anti-p in low cell density cultures, and do not secrete Ig at any cell density, unless T cell-derived factors are provided (19,25). Presumably, LPS and anti-/z prime the B cells by inducing them to express receptors for antigen nonspecific factors that mediate proliferation (e.g., BCGF) or differentiation (e.g., T cell replacing factor [TRF], BCDFs) (18,19,21,(25)(26)(27). CAS is known to contain several lymphokines, which include interleukins (IL-1, IL-2), BCGF, and conventional TRF.…”

“…Additionally, male BXSB early-life SLE can be transferred with anti-Thy-l.2 + complement (C) treated male bone marrow cells given to thymectomized, lethally irradiated female BXSB recipients. 2 It is now clear that normal B cells require several signals to become activated, to proliferate, and to undergo differentiation to antibody-producing ceils (16,21). In this study we have used in vitro assays for which two or more identifiable signals are necessary to obtain B cell responses and compared lupus mice versus normal control mice in regard to: (a) the number of signals required for activation and differentiation and (b) the magnitude of responsiveness to these signals.…”

Antigen-specific helper T-cell clone supernatant is sufficient to induce both polyclonal proliferation and differentiation of small resting B lymphocytes.

“…The different steps of the stimulation of resting B lymphocytes resulting in proliferation and clonal expansion followed by maturation to the immunoglobulin-secretion stage are not yet fully understood (1)(2)(3)(4)(5)(6). B cells can be stimulated by antigen-specific major histocompatibility complex (MHC)-restricted helper T lymphocytes, which can help antigenspecific B lymphocytes and, in some circumstances, induce a polyclonal stimulation of other B cells (1)(2)(3)(5)(6)(7)(8)(9)(10)(11).…”

Biochemical basis of synergy between antigen and T-helper (Th) cell-mediated activation of resting human B cells.

“…Abbreviations used in this paper: AFC, antibody forming cells; BCGF, B cell growth factor, [Ca2+],, intracellular free calcium concentration; DG, diacylglycerol; DiC8, dioctanoyl 1,2 diacylglycerol; EN, which causes a rise in intracellular free Ca2" concentration ([Ca2+]i), and diacylglycerol (DG) which serves as a cofactor in the activation of protein kinase C (PKC) (4)(5)(6)(7). Functionally, antigen-induced B cell activation serves as a proliferative stimulus and readies the B cell to respond to T cell help (8,9). In contrast to this rather well characterized sequence of antigendependent events, neither the biochemical basis of Th cell induced B cell activation nor the mechanism by which antigen and Th cells synergize in B cell activation have been elucidated.…”