B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice

Abstract

Prion replication in spleen and neuroinvasion after i.p. inoculation of mice is impaired in forms of immunodeficiency where mature B lymphocytes are lacking. In spleens of wild-type mice, infectivity is associated with B and T lymphocytes and stroma but not with circulating lymphocytes. We generated transgenic prion protein knockout mice overexpressing prion protein in B lymphocytes and found that they failed to accumulate prions in spleen after i.p. inoculation. We conclude that splenic B lymphocytes are not prion-replication competent and that they acquire prions from other cells, most likely follicular dendritic cells with which they closely associate and whose maturation depends on them.

Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection

“…Expression of PrP C in either B or T cell compartments sufficed to prevent generation of anti-PrP C titers independent of the amount of PrP C expressed (Table 1). Even small amounts of PrP C expressed solely on B cells in transgenic tg306 mice (20) completely inhibited the induction of anti-PrP titers (Table 1).…”

“…To understand the cellular requirements of tolerance to PrP C , we investigated whether the tissue-specific distribution of PrP determines the outcome of anti-PrP immunization. PrP Cdeficient (Prnp o/o ) mice transgenically expressing PrP C exclusively on B cells (20) or T cells (19) were immunized with mouse PrP REC ͞CFA. Expression of PrP C in either B or T cell compartments sufficed to prevent generation of anti-PrP C titers independent of the amount of PrP C expressed (Table 1).…”

“…The role of T cell tolerance was probed by immunizing Prnp o/o mice that do not express any PrP C , as well as Prnp o/o mice bearing transgenes that direct PrP C expression predominantly to B cells (CD19-PrP and Ig -PrP) (20), T cells (lck-PrP) (19), hepatocytes (Alb-PrP) (19), neurons (NSEPrP), or oligodendrocytes (MBP-PrP). In vitro recall challenges of lymphocytes after immunization showed that B and T lymphocytes from Prnp o/o mice were fully responsive to immunization, whereas expression of PrP by any of the transgenes studied prevented proliferative responsiveness, except for MBP-PrP ϫ Prnp o/o mice, which generated a measurable PrP REC -specific lymphocyte response.…”

Current Concepts and Controversies in Prion Immunopathology

“…Inhibition of the LTβ signaling pathway with a soluble receptor, which depletes FDCs (Mackay and Browning, 1998), abolishes prion replication in spleens and prolongs the latency of scrapie after ip challenge (Montrasio et al, 2000). B-cell-deficient µMT mice (Kitamura et al, 1991) are resistant to prions ip (Klein et al, 1997), most likely because of impaired FDC maturation (Klein et al, 1998;Montrasio et al, 2001). Accordingly, the relative distance between FDCs and splenic nerves controls the velocity of prion neuroinvasion (Prinz et al, 2003a).…”

Priones y enfermedades espongiformes transmisibles

“…Debido a que los linfocitos se asocian estrechamente con las células dendríticas, adquieren de ellas los priones. 8 La isoforma PrP Sc se deposita en humanos o animales, facilitando la neurodegeneración, y puede transmitirse a través de las barreras interespecie. 5 Es por ello que la regulación europea exige que se analice el tejido cerebral de los animales mayores de 30 meses, antes de que sus canales puedan comercializarse como carne.…”