Accumulation of CTLA-4 expressing T lymphocytes in the germinal centres of human lymphoid tissues

CTLA-4, a coreceptor with sequence homology to CD28 is expressed on T cells after activation. Mice deficient for CTLA-4 die young from massive infiltration of many organs by activated T cells, which highlights the essential inhibitory role the coreceptor plays in the regulation of the immune response. To study the prevalence and distribution of CTLA-4 in situ immunohistological analyses were carried out on human tonsils and lymph nodes. Expression of CTLA-4 was restricted to alpha beta T cells, and CTLA-4(+) B cells were not observed. In T-cell areas, 2-10% of T cells were positive for CTLA-4 with similar percentages in the CD4(+) and CD8(+) subpopulations. In the germinal centres (GC) the fraction of CTLA-4(+) T cells was much higher (70-90%). This was due to frequent expression of CTLA-4 on the CD4(+) helper subpopulation. GC CD8(+) T cells were rare and mostly did not express the coreceptor. The CTLA-4(+) T-cell fraction was also over-represented among intraepithelial tonsillar T cells. Cycling (Ki-67(+)) and apoptotic (TUNEL(+)) T cells were never positive for CTLA-4, while a subset of CD25(+) cells did express the coreceptor. Since CTLA-4 is essential for the physiological limitation of the immune response, GC T cells, which are mostly CTLA-4 positive, might be important in this process.