Theis where develop. Progenitor cells from the bone marrow enter the thymus to engage in a complicated developmental process and the ones who make it past various bottlenecks leave the thymus as functional, mature CD4 and CD8 T cells.
In the mouse, the thymus dramatically shrinks with age, a process calledthat severely curtails its output of new, naive, i.e., antigen-inexperienced, T cells, and for long researchers simply extrapolated from mouse that thymic involution must be similarly consequential in humans as well. Important to remember here that the mouse is the most common experimental model for basic immunological research. Hence the assumption ‘Given that adults don’t have a functional thymus‘.
However, over time, the weight of experimental data informs us that the mouse isn’t simply a mini-human, albeit a four-legged, nocturnal, short-lived (maximum lifespan ~2 years) rodent version but rather a species unto itself whose physiological attributes cannot be directly extrapolated to the human (please do imagine my exaggerated eye roll here that it ever even got to the point that something so self-evident even needed saying). Specifically, extrapolating mouse thymus function to human is quite flawed.
This answer describes
- Key differences between mouse and human thymic function.
- Effects of thymectomy on T cell numbers and function in humans.
- Effects of transplant-related thymus impairment in humans.
Key Differences Between Mouse & Human Thymic Function
That a similar process of fewer new T cells coming out of the thymus with age had similar relevance in humans as it does in the mouse was long assumed. However, it turns out naive T cell maintenance is quite a different process in humans, one that makes it less dependent on the thymus over time.
- Circulating naive T cells in humans self-renew ( ), a key difference in kind from naive mouse T cells. Specifically, this groundbreaking study (n=45) showed that the circulating naive T cell pool in elderly humans comprised 10% recent thymic emigrants and 90% self-proliferating (homeostatic proliferation), proportions that were exactly reversed in aged mice. Other studies ( ) by other groups including an in silico modeling approach ( ) have since corroborated that self-renewal following their emergence from the thymus is a major feature of human naive T cells. Such renewal depends on local levels of IL-7 ( ) and some other cytokines.
- While short-lived in mice ( ), naive T cells are very long lived in humans ( ).
- Human thymic output may be already less relevant by the 20s since there is little evidence of increasing turnover of circulating naive T cells between 20 and 70 years of age ( ). This implies that already by the 20s, the human thymus has pushed out T cell specificities most biologically relevant for an individual to maintain their immunity during their lifetime.
- Though human thymus begins to involute (reduces its output) early in life, it still remains active until beyond the 60s, only abruptly crashing in the 80s ( ). Thus, blunt extrapolation from mouse thymus involution rates to humans is not only inaccurate but also inherently flawed because even the aged human thymus retains measurable capacity to generate new T cells (see below from , emphasis mine).
‘As an individual ages, the thymus involutes and the output of new T cells falls significantly [38–40]. In 1985, Steinman et al elegantly demonstrated that thymic function gradually starts decreasing from year one of life [38,39]. The observation of dual components of the human thymus, the true thymic epithelial space, in which thymopoiesis occurs, and the non-epithelial non thymopoietic perivascular space [38,39], was critical to the current understanding of thymic atrophy. The expansion of the perivascular space (adipocytes, peripheral lymphocytes, stroma) with age results in a shift in the ratio of true thymic epithelial space to perivascular space. The thymic epithelial space shrinks to less than 10% of the total thymus tissue by 70 years of age. When extrapolated, Steinman’s data suggest that the thymus would cease to produce new T cells at approximately 105 years of age (Figure 1) …We and others have also demonstrated that while the thymopoietic area of the human thymus decreases with age, the thymopoietic potential per cell, as measured by sjTRECs  or by TCR ligation-mediated polymerase chain reaction , remains constant at least until approximately 50 years of age [43,45,47–50].’
Such data help understand what had long remained a conundrum, why the naive human T cell population only shrank modestly with age (8, 9,, ), a reduction not in line with the much more rapid pace and extent of thymic involution. Since circulating naive human T cells appear to both hang around longer and be capable of proliferating (homeostatic proliferation) to maintain themselves, in practical terms, this means with age, human T cell repertoire depends less on a functioning thymus, relying instead on maintaining what’s already emerged from the thymus, a difference in kind from the mouse that makes the human T cell system more resilient to withstand damage to the T cell generating capabilities of the thymus. Repertoire refers to the antigen specificities of individual T cell TCRs ( ), with a broader diversity reflecting better anticipatory preparedness. After all, being prepared to specifically engage with antigens not previously encountered is the calling card of the .
- Homeostatic proliferation is more important for CD4 rather than CD8 T cell maintenance ( ), which may be why even the very old have a measurable naive CD4 T cell pool ( ) and why impact of aging is greater for human CD8 T cells.
- None of this negates the importance of the thymus in introducing T cells with new specificities, i.e., T cells with TCRs capable of recognizing new antigens (epitopes). After all homeostatic proliferation can only maintain, not expand, the existing T cell repertoire, a function that’s the sole purview of the thymus. To quote from (emphasis mine),
‘Although these data show that in terms of naive T cell numbers created per day, peripheral T cell proliferation by far exceeds thymic output in human adults, the thymus may still have an essential role – if only because new T cell specificities can only be created by the thymus.’
Effects of Thymectomy on T cell Numbers & Function in Humans
At 1 in 100 newborns, congenital heart disease is among the most common of birth defects (). Over the past 30 years, having become safer and thus routine, open-heart surgery is increasingly used to correct these defects. However, this also often requires complete or partial thymectomy (thymus removal) since the thymus blocks surgical access to the heart and large vessels, especially in newborns. Researching immune function in such thymectomized individuals in turn provides valuable information on the consequences of such thymectomy.
- One study ( ) on neonatally thymectomized children examined impact in either the short- (within 1 to 5 years, n=17 and 19 healthy controls) or longer-term (at least 10 years later, n=26 and 11 healthy controls) and found it drastically affects T cell diversity (measured as range of TCRs) in the short-term but that the thymus at such a young age is capable of some degree of regeneration since diversity is restored in later life.
- Another study ( ) found rates of autoimmunity and allergy among the neonatally thymectomized (n=7) to be similar to healthy controls (n=7).
- Though both degree (partial versus total) ( ) and age ( ) at thymectomy influence outcome on T cell number and function, they don’t affect general health on the whole apart from a tendency for exaggerated responses to cytomegalovirus (CMV) ( ). How to explain this? One plausible explanation could be that thymectomy provides impetus for increased plasma IL-7 levels ( ), which in turn could support T cell homeostatic proliferation ( , ).
- >20 years post-thymectomy, patients infected with CMV had fewer circulating naive T cells and reduced TCR diversity ( ) and delayed primary antibody response to tick-borne encephalitis vaccination (22, 23).
Since routine neonatal open-heart surgery and its attendant thymectomy are at 30 years or so of recent vintage, lifelong impact on immunity and health is still work in progress. However, these and other studies suggest impact is individual, hard to predict and highly influenced by chronic infections, especially CMV.
Effects of Transplant-related Thymus Function or Impairment in Humans
Preparing the body for transplant (transplant conditioning regimens) entails the kinds of preparatory treatments (irradiation, chemotherapy, steroids) that severely damage the thymus, impairing its capacity to push out new T cells.
- Adequate thymic recovery was observed after autologous stem cell transplant
- Even in those with severe autoimmune diseases (n=10, age range 16 to 49 years old, n=21 controls, age range 20 to 55 years old) (24).
- In Multiple Sclerosis (MS) patients (n=7, age range 28 to 53) ( ).
- Adequate thymic recovery was observed after heterologous kidney transplant (n=48 patients, 39 controls) ( ).
- One study (
) of 32 adult breast cancer patients treated with autologous peripheral blood stem cell transplant (age range 30 to 69) found thymic recovery to be strictly a function of age, with measurable thymus enlargement (sign of recovery) post-transplant in
- 4 of 5 of those 30 to 39 years old
- 6 of 13 in those 40 to 49 years old.
- Only 2 of 14 in those >50 years old.
Given its capacity for some regeneration as well as its ability to continue to push out new T cells even later in life, albeit at markedly lower rates, no surprise that the human thymus can bounce back after neonatal thymectomy as well as from transplant-related damage. Degree of recovery is also unsurprisingly a function of age and environment. As well, unlike their mouse counterparts, human naive T cell capacity for self-propagation helps maintain them even into old age.
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