X-linked hyper IgM (HIGMX-1) is a rare inherited immune deficiency disease resulting from a defect in the gene for CD40 ligand (CD40L). Patients exhibit an heterogenous phenotype with normal or elevated IgM, recurrent bacterial infections with or without opportunistic infections, autoimmune disease, or lymphoproliferative disease. Data from CD40 or CD40L gene-targetted mice suggests that, in addition to the defect in humoral immunity, CD40L/CD40 interaction is necessary for T cell priming. Unlike gene-targetted mice, HIGMX-1 patients express mutated mRNA, and heterogeneity of the disease may partly result from differences in the expressed protein. We have investigated two patients with HIGMX-1 who have a deletion of the third exon of CD40L. Analysis of the CD40L genomic DNA showed that the deletion in the third exon resulted from different genomic mutations. The first patient, an 8 year old boy of Chinese origin, had a deletion of the first nucleotide in the donor site of exon 3 while the second patient, a 23 year old boy of Italian origin, had a point mutation (a->g) at the -2 position in the acceptor site of exon 3. The patients' clinical disease differs in levels of IgM and IgA and in the development of opportunistic infections. The differences in clinical phenotype may be related to differences in environmental exposure, or may, in part result from differences in the effect of the differing genomic mutations on mRNA splicing and skipping of the third exon. Next, we examined the effect of the CD40L deficiency on T cell priming in the second patient. In contrast to CD40L-deficient mice, this patient demonstrated reactivity against recall antigens by T cell proliferation in-vitro and by positive delayed-type hypersensitivity skin testing in-vivo. Also, the patient's circulating T cells contained a primed population of CD4+ T cells as determined by CD45RO expression; and in his mother, an obligate carrier of HIGMX-1, only 47% of the CD4+/CD45RO+ T cells expressed CD40L upon stimulation compared to 80% of control CD4+/CD45RO+ T cells indicating that normal CD40L did not provide an advantage for T cell priming. These results suggest that at least some patients with HIGMX-1 have no defect in T cell priming.