Frontline Science: Exhaustion and senescence marker profiles on human T cells in BRGSF‐A2 humanized mice resemble those in human samples

• Published in: Journal of leukocyte biology Vol. 107; no. 1; pp. 27 - 42
• Main Authors: Labarthe, Laura, Henriquez, Soledad, Lambotte, Olivier, Di Santo, James P., Grand, Roger, Pflumio, Françoise, Arcangeli, Marie‐Laure, Legrand, Nicolas, Bourgeois, Christine
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.01.2020
• Subjects: adipose tissue; Apoptosis; Blood cells; Bone marrow; CD34 antigen; CD4 antigen; CD57 antigen; Cell death; Cord blood; Immune system; Immunological memory; immunoregulation; Immunotherapy; KLRG1 protein; Lymphocytes; Lymphocytes T; Memory cells; PD-1 protein; PD‐1; PD‐L1; Senescence; Spleen; PD-L1; adipose tissue; immunoregulation; PD-1; bone marrow
• ISSN: 0741-5400; 1938-3673; 1938-3673
• DOI: 10.1002/JLB.5HI1018-410RR

This work sought to confirm the human‐like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2KO IL2rgcKO SirpαNOD Flk2KO HLA‐A2HHD (BRGSF‐A2) mouse reconstituted with human CD34+ cord blood cells. With regard to senescence markers, the percentage of CD57+ T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1+ hCD8+ T cells. With regard to exhaustion markers, the percentage of programmed death 1 (PD‐1+) T cells was higher in the BM than in the spleen or blood; the same was true for TIGIT+ hCD4+ cells. These tissue‐specific differences were related to both higher proportions of memory T cells in BM and intrinsic differences in expression within the memory fraction. In blood samples from HIS mice and healthy human donors (HDs), we found that the percentage of KLRG1+ cells among hCD8+ T cells was lower in HIS compared to HDs. The opposite was true for CD4+ T cells. Unexpectedly, a high frequency of KLRG1+ cells was observed among naive T cells in HIS mice. CD57 expression on T cells was similar in blood samples from HIS mice and HDs. Likewise, PD‐1 expression was similar in the two systems, although a relatively low proportion of HIS hCD4+ T cells expressed TIGIT. The BRGSF‐A2 HIS mouse's exhaustion and senescence profile was tissue specific and relatively human like; hence, this mouse might be a valuable tool for determining the preclinical efficacy of immunotherapies. Exhaustion and senescence profiles in BRGSF‐A2 HIS mice are similar to those observed in humans.