Regulation of T cell CD5 levels by BTLA

Abstract

Abstract Many coinhibitory receptors are absent from naïve T cells and upregulated upon activation. In contrast, there are a small number of coinhibitory receptors expressed constitutively by naïve T cells, including CD5, BTLA, and VISTA. The relationship between these constitutively expressed coinhibitors is unknown. We examined the relationship between the constitutively expressed BTLA and CD5 in T cell ontogeny. We found an inverse relationship between CD5 and BTLA expression levels, with low BTLA expression in the thymus and higher BTLA expression in the periphery, corresponding with high and low CD5 expression, respectively. To determine if there is a causal relationship between BTLA expression and CD5 expression, we examined CD5 expression in wild type (WT) vs. btla−/− T cells. Interestingly, btla−/− T cells consistently expressed higher levels of CD5 both in thymic and splenic CD4 and CD8 T cells, indicating that BTLA expression directly or indirectly determines the level of CD5 expression broadly across T cells. In contrast, the loss of an inducible coinhibitor, PD-1, only affected CD5 levels on splenic CD8+ T cells. The loss of BTLA expression early in ontogeny might alter the TCR repertoire indirectly affecting CD5 levels, or instead its loss might affect CD5 expression rapidly within mature T cells. To examine the latter, we deleted btla by administering tamoxifen to adult btlafl/fl CreERT2+/− mice and WT CreERT2+/− controls. Loss of btla in adults led only to a transiently heightened CD5 expression. Together our data indicates that loss of BTLA early, but not later in ontogeny, leads to a long-term increase in CD5 expression by T cells. Such calibration of CD5 levels early in ontogeny might serve to reduce autoimmunity. Funded by the CIHR, NSERC, and an AAI fellowship; btlafl/fl mice provided by the La Jolla Institute for Immunology.