Igh‐1b‐specific CD4⁺CD8⁻ T cell clones of the T_h1 subset selectively suppress the Igh‐1b allotype in vivo

Abstract

The demonstration of major histocompatibility complex (MHC)-restricted T helper (Th) cells specific for peptides from the variable (V) regions of syngeneic immunoglobulin (Ig) (idiopeptides) opens the possibility that Th cells regulate B cell functions via idiopeptide-based cognate T-B interactions. As a model for such interactions we investigated the influence of Ig allotype-specific T cells on the differentiation of H-2-syngeneic B cells expressing that particular Ig allotype. We established a BALB/c (H-2d, Iga) CD4+CD8- T cell line and clones of the Th1 subset (interleukin 2+, interleukin 4-, interferon-gamma+, tumor necrosis factor-alpha+) that recognized Igh-1 (IgG2a) of the b allotype (Igh-1b) together with I-Ad. These T cells specifically suppressed surface Igh-1b+ B cells in vitro and in vivo. In 12 out of 15 6-week-old (BALB/c X B10.D2)F1 mice neonatally injected with Igh-1b-specific T cells, the serum Igh-1b concentrations were less than 5% of the levels in the controls. Thus, allotype suppression can be accomplished solely by adoptive transfer of Igh-1b-specific CD4+ T cells. The in vivo suppression was specific for Igh-1b+ B cells as the recipients' levels of Igh-1a and Igh-4b (IgG1b) were unaffected. The V beta 14-specific anti-T cell receptor (TcR) monoclonal antibody 14-2 inhibited activation of hybridomas derived from two of the clones. Collectively the data indicate that suppression resulted from cognate interactions between allopeptide-specific TcR alpha/beta+ T cells and normal unmanipulated B lymphocytes presenting their endogenous Igh-1b in association with MHC class II molecules. The data support the possibility that normal B cells can be suppressed by idiopeptide-specific T cells in vivo.

Engagement of the B lymphocyte antigen receptor induces presentation of intrinsic immunoglobulin peptides on major histocompatibility complex class II molecules

“…We previously established that spleen cells from IgCHb I-Ad strains stimulated the B5 hybridoma in the absence of exogenously added Ag [9]. Constitutive presentation was weak or undetectable after changing animal facilities and introducing specific pathogen-free conditions (unpublished).…”

“…. Whereas clone B5 accordingly failed to respond to intact soluble IgG2a" [9], it nevertheless cross-reacted, although weakly, with the synthetic y2a" 435-451 selfpeptide [lo]. Encouraged by the results with IgCH allogeneic B lymphocytes, we tested whether anti-Ig could induce recognition of the sIgG2a'-expressing BALBk lymphoma A20.…”

“…mAb G12-47/30 (mouse IgG1") (see [9]) specific for the mouse IgG2ab allotype was purified from hybridoma culture SN by acid elution from protein G-Sepharose (Pharmacia Fine Chemicals, Uppsala, Sweden) and an F(ab'), preparation was obtained by pepsin digestion, as described [15]. The 187.1.10 hybridoma was purchased from ATCC and its secreted rat IgGl mAb specific for mouse Ig x chains [16] was isolated from hybridoma SN on mouse y-globulinconjugated Sepharose (Pharmacia).…”

“…The T cell hybridoma B5 was derived from a CD4' clone originating in an IgG2ab-immunized BALB/c mouse [9] and recognizes the y2ab 435-451 (Kabat numbering) allopeptide/ I-Ad complex [ 101. Splenic single-cell suspensions were prepared by standard procedures and when indicated, yirradiated by a 137cesium-equipped IBL 437 C device (Cis Bio International, Gif sur Yvette, France).…”

“…It has been hypothesized that Ig V region (idio)peptide-specific Th regulate B lymphocytes [3,4] and represent a line of defense against B cell neoplasms, on which the clonotypic Ig represents a tumor-specific Ag [5]. In support of these contentions, it has been demonstrated that B cells present peptides derived from their intrinsic Ig in complex with MHC class I1 molecules , and thus participate in stimulatory [12] and suppressive [9] cognate Th/B interactions across TcWIg peptide/MHC class I1 bridges. The number and efficiency of Th clones recruited depend on the repertoire of Ig peptides presented and the copy number of each determinant on the B cell surface.…”