Most hematopoiesis involves continuous production of differentiated lineages to offset continuous loss. Some capacity for facultative “tuning” of output can occur in emergencies, such as severe blood loss or infection. By contrast, lymphopoiesis generates a diverse repertoire of unique antigen receptors on individual clones (gray-outlined circles), followed by elimination of strongly autoreactive clones, and export to periphery in anticipation of immune response. In an acute or low-level persistent immune response, a sole T cell clone with correct receptor (red outline) is activated by antigenic plus costimulatory signals (collectively represented by lightning bolts), causing cell division, which is accompanied by differentiation and self-renewal by clonally related descendants of the selected cell. When the threat entails high-level, repetitive activation, at least two separable problems of failing immunity can ensue: (i) acquired dysfunction of differentiated cells, often referred to as “exhaustion,” and (ii) eroding abundance of self-renewing cells, which can result in diminished output of fresh, differentiated cells or complete loss of the clone and its descendants. It is speculated that prevention of erosion of self-renewal may be more actionable than reversal of differentiated cell dysfunction.