The Role of T Cell Help in the Production of Antibodies Specific for Galα1–3Gal

Abstract

The majority of xenoreactive natural Abs in humans recognize the carbohydrate Ag present on pig tissue, Galα1–3Galβ1–4GlcNAc-R (αGal), synthesized by the enzyme UDP galactose:β-d-galactosyl-1,4-N-acetyl-d-glucosaminide α(1–3)galactosyltransferase or αGT. Using αGT knockout mice (GT0 mice), which like humans produce serum Abs that bind αGal, we examined the role of T cells in production of Abs specific for αGal. GT0 mice were crossed with TCR-β knockout mice (TCR-β0) to generate double-knockout mice (GT0/TCR-β0). While GT0/TCR-β+ mice exhibited an age-dependent increase in the serum titer of natural Abs specific for αGal, a similar increase was not observed in GT0/TCR-β0 mice, and the titer of αGal-specific Abs in double knockouts was significantly lower than in age-matched GT0/TCR-β+ mice. Immunization with pig cells resulted in a significant increase in the serum titer of αGal-specific Abs in GT0/TCR-β+ mice, but had no effect on the level of αGal-specific serum Abs in GT0/TCR-β0 mice. Treatment of GT0/TCR-β+ mice with anti-CD40L Abs before immunization with pig cells prevented sensitization to αGal. Our data suggest that the majority of αGal-specific Abs are T cell dependent and that production of αGal-specific Abs after sensitization can be prevented by blocking costimulatory pathways.

Peritoneal Cavity B Cells Are Precursors of Splenic IgM Natural Antibody-Producing Cells

“…However, we previously showed that the MLN was not a major site for the production of either anti-Gal or total IgM Ab after rabbit RBC immunization i.p (13). Although evidence suggests that induced anti-Gal IgM Ab responses are largely T cell dependent in Gal knockout mice (36), this response appears to be dependent on the ␣␤ TCR-bearing class of T cells (37) and not on ␥␦ T cells (A. Thall, unpublished observations). Baseline anti-Gal IgM levels in Gal knockout mice are not fully dependent on T cells (A. Thall, unpublished observations), and T cell depletion seems to actually increase the baseline anti-Gal NAb levels (38).…”

B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-αGAL–producing B-1 cells

“…52,53 However, we observed similar frequencies of cells with anti-␣Gal receptors in GalT Ϫ/Ϫ Cr2 Ϫ/Ϫ compared with GalT Ϫ/Ϫ mice, and the same B-1b-cell population appeared to be responsible for anti-␣Gal production in both groups. The relationship between B-1a and B-1b cells has not been well defined.Although there is some controversy regarding NAb regulation by T cells, 54 we have observed that baseline anti-␣Gal NAb levels are increased by depletion of T cells. 55 In contrast, the induced anti-␣Gal IgM response is largely T-cell dependent.…”

“…55 In contrast, the induced anti-␣Gal IgM response is largely T-cell dependent. 54,56 Both baseline and induced anti-␣Gal levels were enhanced by nonhematopoietic CR1/CR2 expression, suggesting a role for FDC CR1/CR2 expression in both T-independent and T-dependent Ab responses.Total serum IgM levels were unaffected by the presence or absence of CR1/CR2 on hematopoietic and/or nonhematopoietic cells in our model. Our previous studies showing that anti-␣Gal-and total IgM-producing cells belong to the same B-cell subset 9 led to the expectation that total IgM levels would be reduced in mice lacking nonhematopoietic cell CR1/CR2 expression.…”

Gene Therapy Progress and Prospects: Gene therapy in organ transplantation

“…To determine the extent to which a preformed immune response was a barrier to the induction of molecular chimerism, aGT knockout mice were immunized with aGal-expressing pig cells. Since aGal is a T-dependent antigen 28 this immunization resulted in T-cell priming and increased titers of antiGal antibodies. Despite high titers of serum aGal-specific antibodies in immunized hosts, molecular chimerism could be established by increasing the dose of transduced bone marrow used for reconstitution of lethally irradiated recipient.…”