Hyper-IgM syndrome is caused by a defect in which of the following?

Hyper-IgM syndrome is primarily caused by a defect in the CD40 ligand (CD40L), which plays a crucial role in the interaction between T and B cells. In a typical immune response, T cells express CD40L that binds to CD40 on B cells, facilitating crucial processes such as class switching and somatic hypermutation. These processes allow B cells to produce different classes of antibodies, such as IgG, IgA, and IgE, which are essential for an effective immune response.

In individuals with Hyper-IgM syndrome, the defect in CD40L results in the inability of B cells to undergo class switching. Consequently, there is an accumulation of immunoglobulin M (IgM) but a deficiency in other antibody isotypes, leading to an increased susceptibility to infections.

When considering the other options, defects in the CD28 receptor typically involve T-cell activation more broadly and may lead to different immunological issues, while defects in B-cell maturation and T-cell activation do not specifically result in the hyper-IgM profile characteristic of this syndrome. The pivotal role of CD40L in class switching is what distinctly establishes its connection to Hyper-IgM syndrome.