Elite-level physical performance pushes the boundaries of human physical capacity. The immune system extensively contributes to this effort by its continuous maintenance of skeletal muscle and other active tissues, orchestrating post-exercise recovery, and as an important integrated sensor network throughout the body. A complexly regulated system with wide ranges of in- and outputs, cutting-edge technologies can enable an increasingly individualized approach without the need for translation of results to human biology. The systems immunology idea of resource allocation plays a major role throughout the human life cycle, and great attention should be directed at the prioritization of these resources to either acute physical performance or immune function, particularly in injury- or disease-prone contexts such as elite athletics. As such, this review aims at emphasizing the systems immunology perspective on immune system function and human performance, and its integration with other systems and factors relevant in physical activity such as nutrition, recovery, and sleep. It also attempts to revisit the previous concept of a J-shaped curve relationship between performance levels and infection risk. Finally, it will point out key questions that remain unanswered, such as the implications of life-long training on the composition of the immune system, resource allocation in the competition between immune function and acute exercise, and what implications such adaptations might have for athletic performance. Such an updated, integrated, systems-level perspective on immunity may guide future research about improved recovery in athletes and more individualized exercise training approaches.
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