Requirement for CD28 May Not Be Absolute for Collagen-Induced Arthritis: Study with HLA-DQ8 Transgenic Mice

Abstract

CD28 is required to achieve optimal T cell activation to an Ag. To determine the role CD28 costimulation plays in collagen-induced arthritis, we have generated DQ8 transgenic, CD28-deficient mice. DQ8 mice deficient for CD28 had comparable numbers of CD4 and CD8 T cells as DQ8.CD28+/+ mice. DQ8.CD28−/− mice develop collagen-induced arthritis with delayed onset and less severity than DQ8.CD28+/+ mice. T cells from DQ8.CD28−/− mice did not respond to type II collagen efficiently in vitro, although the response to DQ8-restricted peptides was similar to that in the parent mice. There was no functional defect in T cells as observed by proliferation with Con A. Cytokine analysis from in vitro study showed the production of high levels of the inflammatory cytokine, IFN-γ, in response to type II collagen. We observed an increase in CD4+CD28−NKG2D+ cells after immunization, suggesting an important role for cells bearing this receptor in the disease process. CD28−/− mice also have an increased number of DX5+ cells compared with CD28+/+ mice, which can lead to the production of high levels of IFN-γ. DQ8.CD28−/− mice had an increased number of cells bearing other costimulatory markers. Cells from DQ8.CD28−/− mice exhibited a lower proliferation rate and were resistant to activation-induced cell death compared with DQ8.CD28+/+ mice. This study supports the idea that CD28 plays a crucial role in the regulation of arthritis. However, in the absence of CD28 signaling, other costimulatory molecules can lead to the development of disease, thus indicating that the requirement for CD28 may not be absolute in the development of arthritis.

To B or not to B: Role of B cells in pathogenesis of arthritis in HLA transgenic mice

“…These observations suggested a crucial role of Ii chain in cell selection and the proper functioning of HLA molecules in transgenic mice. In addition to the chaperone molecule such as Ii, costimulatory molecules like CD28 also function normally in transgenic mice as observed by studies using DQ8.CD28−/− mice [26]. These studies show that the HLA transgenes work with endogenous molecules suggesting the transgenic mice are functional and can provide good models to study various HLA-associated human diseases.…”

Role of HLA class II genes in susceptibility/resistance to inflammatory arthritis: studies with humanized mice

“…CD4 + T cells from DQ8.CD28 −/− mice showed reduced in vitro responses but could be primed to antigen to mount primary and secondary responses. Using DQ8.CD28 −/− mice, we have shown that CD28 is not required for development of CIA, although in the absence of CD28 onset of disease was delayed (66). These studies suggested that for optimal response, CD28 is required, but in the absence of CD28, other costimulatory molecules can compensate for the function of CD28.…”

Oncogenic stress sensed by the immune system: role of natural killer cell receptors

“…NKG2D is expressed by virtually all NK cells and activated CD8 + T cells, and subsets of γδ T cells and NKT cells 61, 62. In certain conditions, NKG2D is also expressed by CD4 + T cells, at least in humans63–67.…”