B-1 B Cells Mediate Required Early T Cell Recruitment to Elicit Protein-Induced Delayed-Type Hypersensitivity

Abstract

We define the initiation of elicited delayed-type hypersensitivity (DTH) as a series of processes leading to local extravascular recruitment of effector T cells. Responses thus have two sequential phases: 1) 2-h peaking initiation required for subsequent recruitment of T cells, and 2) the late classical 24-h component mediated by the recruited T cells. We analyzed DTH initiation to protein Ags induced by intradermal immunization without adjuvants. Ag-spceific initiating cells are present by 1 day in spleen and lymph nodes. Their phenotypes, determined by depletion of cell transfers by mAb and complement, are CD5+, CD19+, CD22+, B220+, Thy1+, and Mac1+, suggesting that they are B-1 B cells. DTH initiation is absent in μMT B cell and xid B-1 cell deficient mice, is impaired in mice unable to secrete IgM, and is reconstituted with 1 day immune serum, suggesting that early B-1 cell-derived IgM is responsible. Study of complement C5a receptor-deficient mice, anti-C5 mAb neutralization, or mast cell deficiency suggests that DTH initiation depends on complement and mast cells. ELISPOT assay confirmed production of Ag-specific IgM Abs at days 1 and 4 in wild-type mice, but not in B-1 cell-deficient xid mice. We conclude that rapidly activated B-1 cells produce specific IgM Abs which, after local secondary skin challenge, form Ag-Ab complexes that activate complement to generate C5a. This stimulates C5a receptors on mast cells to release vasoactive substances, leading to endothelial activation for the 2-h DTH-initiating response, allowing local recruitment of DTH-effector T cells.

Identification of Initiator B Cells, a Novel Subset of Activation-Induced Deaminase-Dependent B-1-Like Cells That Mediate Initiation of Contact Sensitivity

“…Since initiator B cells are IgM positive and our past studies have demonstrated that CS initiation is mediated by IgM Abs (3,4,7,19), Class-switch recombination resulting in isotype switching can be excluded, as can gene conversion which is not known to occur in mice (20). The formal possibility remains that some other, as yet unidentified, biological function of AID is required for the development of CS initiation.…”

“…B cells are divided into several populations including B-2, B-1a and b, and marginal zone B cells, and recent evidence strongly suggests the existence of additional populations (10). Our previous studies identified the B cells responsible for CS initiation as a population of B-1 cells, based on their expression of CD11b in the PerC and CD5 in the spleen (1,2,4,7). However, the modern definition of B-1 cells has been expanded to include high expression of IgM and low expression of IgD, among others (see below) (11,12), which necessitates a re-evaluation of the identity of the B cell responsible for DTH/CS initiation.…”

“…Following sensitization they are activated to migrate to the spleen and produce IgM (3,5,6). These Abs enter the circulation and, upon local challenge to the skin, induce a mild, local vasoactive response that peaks 2 h after challenge (7,8). Evidence suggests that this early response is required to recruit rare Agspecific T cells to the local site of exposure, since interference with any step in this pathway or with mechanisms of T cell recruitment within the 2-h window postchallenge, effectively prevents the subsequent development of the severe, delayed inflammatory response (3,4,9).…”

p-Phenylenediamine and Risk of Sensitization in Children

“…In the induction phase, the hapten penetrates the skin barrier, which activates dendritic cells that migrate to draining lymph nodes with priming of naïve T cells and later activation of hapten-specific T cells [45][46][47][48]. The elicitation phase normally begins with renewed exposure to the hapten, when the hapten is presented to hapten-specific T cells by allergen-presenting cells with the result of local cytokine and chemokine release [45,49]. These mediators both have proinflammatory responses and recruit other inflammatory cells, which makes the skin develop acute dermatitis with erythema, edema, infiltration, and vesicles.…”

Cerebral Pathology in Immunodeficient Gnotobiotic Laboratory Mice

“…Gnotobiotic immunologically-active molecule mutant or knockout mice are commonly used in studies on immunological mechanisms and animal models of human autoimmune diseases (e.g., SABELKO-DOWNES et al 2000;MACPHERSON et al 2001;PAUL et al 2003;SZCZEPANIK et al 2003). In the course of a routine histological examination of the cerebra of pathogen-free autoimmunity prone and immunological molecule knockout mice, moderate to severe pathological changes in their cerebra were observed.…”