Differential impact of self and 1 environmental antigens on the 2 ontogeny and maintenance of CD 4 + T 3 cell memory 4

Laboratory mice develop populations of circulating memory CD4+ T cells in the absence 14 of overt infection. We have previously shown that these populations are replenished from naive 15 precursors at high levels throughout life (Gossel et al., 2017). However, the nature, relative 16 importance and timing of the forces generating these cells remain unclear. Here, we tracked the 17 generation of memory CD4+ T cell subsets in mice housed in facilities differing in their ‘dirtiness’. 18 We found evidence for sequential naive to central memory to effector memory development, and 19 confirmed that both memory subsets are heterogeneous in their rates of turnover. We also 20 inferred that early exposure to self and environmental antigens establishes persistent memory 21 populations at levels determined largely, though not exclusively, by the dirtiness of the 22 environment. After the first few weeks of life, however, these populations are continuously 23 supplemented by new memory cells at rates that are independent of environment. 24