THYMIC SELECTION AND ADAPTABILITY OF CYTOTOXIC T-LYMPHOCYTE RESPONSESIN TRANSGENIC MICE EXPRESSING A VIRAL PROTEIN IN THE THYMUS

Upon primary challenge with lymphocytic choriomeningitis virus (LCMV), H-2(d) (BALB/cByJ) mice mount a cytotoxic T lymphocyte (CTL) response to a single immunodominant domain of the viral nucleoprotein (NP) but no detectable response to the viral glycoprotein (GP). To manipulate this CTL response, the viral NP gene was expressed in the thymus and p eripheral T lymphocytes using the murine Thy1.2 promoter. As a result, such Thy1.2-NP (H-2(d)) transgenic (tg) mice deleted their high-affin ity anti-LCMV-NP CTL, but generated equal numbers of lower-affinity NP CTL. Further, they made an alternative anti-LCMV-GP CTL response that is not normally found in non-tg mice indicating a hierarchial control of the CTL response. Unlike the H-2(d) mice, H-2(b) (C57B1/6J) mice n ormally mount a CTL response to both LCMV-GP and -NP. When the LCMV-NP was expressed using the Thy1.2 promoter in these H-2(b) mice, the LCM V-NP-specific CTL response was completely aborted and no CTL to new, a lternative viral epitopes were generated. Dilutions of H-2(b) or H-2(d ) NP peptides indicated that 3-4 logs less H-2(b) NP peptide was requi red to sensitize syngeneic target cells for CTL-specific lysis, sugges ting that the differing affinities of H-2(b) and H-2(d) major histocom patibility complex molecules for their peptides likely account for the total removal of NP CTL in the H-2(b) mice but only partial removal i n H-2(d) mice made to express thymic NP. Thymic grafting experiments d one with thymi from newborn Thy1.2-NP tg mice show that selection proc esses studied in this model are of central (thymic) origin and are not caused by Thy1.2-positive LCMV-NP-expressing T lymphocytes in the per iphery.