**2. Effects on the maturation of immune cells**

Cells that make up our immune system are derived from hematopoietic stem cells (HSC). These HSC will give rise to common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). After several differentiation steps, CMPs will give raise to myeloid cells (granulocytes, monocytes, macrophages, and dendritic cells) and CLPs to lymphoid cells (B and T lymphocytes and NK cells). All of these cells are involved in natural and/or specific immunity.

A number of studies have analyzed the impact of spaceflight on the development of cells belonging to the myeloid lineage (or myelopoiesis). A decrease in the number of granulocyte and monocyte progenitors in rodents that have been in space or subjected to anti-orthostatic suspension (a model commonly used in the laboratory to reproduce many of the physiological changes observed in flight) has been demonstrated [20, 21]. The culture of human CD34+ progenitors in flight has confirmed the inhibitory effect of microgravity on erythropoiesis (red blood cell production) [22]. Other studies have shown that the stressors encountered during spaceflight impact lymphocyte development (or lymphopoiesis). Diverse animal models have been used to address this question, such as mouse or the Iberian ribbed newt (*Pleurodeles waltl*, a urodele amphibian). The latter lends itself well to the constraints associated with space experiments and has all the cardinal elements of the mammalian immune system [23]. It has notably been observed that *P. waltl* larvae developed on board the ISS exhibit changes in the expression of IgM heavy-chain transcripts as well as a disruption in the expression of the Ikaros gene encoding transcription factors required for lymphopoiesis, suggesting that the latter could be weakened under spatial conditions [24]. This hypothesis was then confirmed in mice subjected to 21 days of anti-orthostatic suspension, which corresponds to a long-term mission at the human scale. It has been shown that this model induces a decrease in the number of CLPs and cells at the pro-B, pre-B, immature B, and mature B stages in the femoral bone marrow of suspended mice compared to control mice [25]. Furthermore, various causes of this weakening have been identified, such as a decrease in signal transduction by the interleukin-7 receptor and a decrease in the expression of transcription factors essential for B-cell development within the bone marrow. It has also been noted that this decrease in B lymphopoiesis is coupled with the remodeling of the bone tissue induced by the suspension, thereby reminding that all physiological systems interact within an organism and that these interactions have to be taken into account when analyzing the impact of stressors such as modeled microgravity. Finally, this sensitivity of hematopoiesis and the link with bone remodeling was confirmed in mice embarked on board the BION-M1 satellite for 30 days [26]. A decrease by a factor of two in the number of

B lymphocytes present in the bone marrow and a statistically significant decrease in the expression of factors required for the development of immune and bone cells were observed 7 days after returning to Earth but not on landing (**Figure 2**). This time delay can be explained by the fact that bone loss worsens after landing [27].

Note that in addition to the explanations presented above, glucocorticoids produced in response to chronic stress may contribute to altering B lymphopoiesis. Indeed, it has been demonstrated that continuous administration of corticosterone, via a subcutaneous implant, induces reprogramming of lymphopoiesis in mice, with a reduction of 30–70% of pro-B, pre-B, and immature B cells after 24 hours and a drop of 70–80% of pro-B and pre-B cells after 36 hours of treatment [29].

T lymphopoiesis (T-cell development in the thymus) is also affected by microgravity, as a decrease in T cells was observed in double-positive (CD4<sup>+</sup> CD8+ ) and single-positive (CD4+ or CD8+ ) maturation stages, when murine fetal thymuses were cultivated under simulated microgravity or spatial conditions [30]. This observation can be explained, at least in part, by the high sensitivity of thymocytes to stress [31]. Indeed, significant changes in mRNA expression from genes known to regulate stress and glucocorticoid receptors were observed in the thymus of mice subjected to a 13-day flight [32]. Another study did analyze the impact on murine T-cell antigen receptor (TCR) of being conceived and born under increased G force (2 G). This study revealed a disruption in TCR signaling and in the diversity of these receptor binding sites [33] (**Figure 3**) required for an individual to be able to specifically recognize peptides derived from the numerous antigens present in the

#### **Figure 2.**

*Analysis of the femur from mice flown for 1 month on board the BION-M1 biosatellite revealed a decrease in the expression of 10 out of 11 proteins involved in immune cell and skeletal development, a decrease of the expression of 17 other immune-related proteins, and a 50% decrease in the number of B cells present in the bone marrow. Furthermore, this study showed that spaceflight effects were aggravated 1 week after landing [26]. Picture of mice in BION-M1 habitat from [28].*

**39**

**Figure 3.**

*Spaceflight-Associated Immune System Modifications DOI: http://dx.doi.org/10.5772/intechopen.88880*

environment; 85% of the TCR repertoire was different in 2 G pups compared to control pups. Thus, the diversity of T-cell antigen receptor repertoire is significantly

*Exposure to hypergravity during pregnancy affects TCR binding sites, thereby suggesting that the protection of the host might be affected [33]. T cells recognize an antigenic peptide on an MHC molecule at the surface of an antigen-presenting cell (APC) (dendritic cell, monocyte, macrophage, B cell). This recognition is ensured by the T-cell receptor (TCR) whose binding site is composed of six small polypeptide loops: two CDR1 loops, two CDR2 loops, and two CDR3 loops. CDR1 and CDR2 loops bind the MHC molecule. CDR3 loops bind the peptide. This figure presents the frequency of hydrophobic, acid, basic and polar amino acids at each position* 

The impact of a model aiming at mimicking socio-environmental stresses experienced by astronauts [34] was then studied. This model involves the chronic exposure of mice to unpredictable socio-environmental stresses of various types (e.g., confinement, isolation, cage tilt, paired housing, perturbed circadian rhythm) and moderate intensity. It was demonstrated that this type of stressors only modifies 25% of the TCR repertoire [35]. Consequently, it appears that a change in the gravitational force has a much greater impact than socio-environmental stresses on

Natural or innate immunity is the body's first line of defense against a pathogen after the skin and epithelial surfaces. It enables a non-specific response to be implemented, involving various types of immune cells such as neutrophils, monocytes,

altered by 2 G exposure, which will likely affect host defense.

*within TCR CDR3 loops from murine pups conceived and born at 1 or 2 G.*

the T-cell antigen receptor repertoire.

**3. Effects on phagocytic and NK cells**

*Spaceflight-Associated Immune System Modifications DOI: http://dx.doi.org/10.5772/intechopen.88880*

#### **Figure 3.**

*Beyond LEO - Human Health Issues for Deep Space Exploration*

or CD8+

single-positive (CD4+

B lymphocytes present in the bone marrow and a statistically significant decrease in the expression of factors required for the development of immune and bone cells were observed 7 days after returning to Earth but not on landing (**Figure 2**). This time delay can be explained by the fact that bone loss worsens after landing [27]. Note that in addition to the explanations presented above, glucocorticoids produced in response to chronic stress may contribute to altering B lymphopoiesis. Indeed, it has been demonstrated that continuous administration of corticosterone, via a subcutaneous implant, induces reprogramming of lymphopoiesis in mice, with a reduction of 30–70% of pro-B, pre-B, and immature B cells after 24 hours and a

drop of 70–80% of pro-B and pre-B cells after 36 hours of treatment [29].

were cultivated under simulated microgravity or spatial conditions [30]. This observation can be explained, at least in part, by the high sensitivity of thymocytes to stress [31]. Indeed, significant changes in mRNA expression from genes known to regulate stress and glucocorticoid receptors were observed in the thymus of mice subjected to a 13-day flight [32]. Another study did analyze the impact on murine T-cell antigen receptor (TCR) of being conceived and born under increased G force (2 G). This study revealed a disruption in TCR signaling and in the diversity of these receptor binding sites [33] (**Figure 3**) required for an individual to be able to specifically recognize peptides derived from the numerous antigens present in the

*Analysis of the femur from mice flown for 1 month on board the BION-M1 biosatellite revealed a decrease in the expression of 10 out of 11 proteins involved in immune cell and skeletal development, a decrease of the expression of 17 other immune-related proteins, and a 50% decrease in the number of B cells present in the bone marrow. Furthermore, this study showed that spaceflight effects were aggravated 1 week after landing [26].* 

gravity, as a decrease in T cells was observed in double-positive (CD4<sup>+</sup>

T lymphopoiesis (T-cell development in the thymus) is also affected by micro-

) maturation stages, when murine fetal thymuses

CD8+

) and

**38**

**Figure 2.**

*Picture of mice in BION-M1 habitat from [28].*

*Exposure to hypergravity during pregnancy affects TCR binding sites, thereby suggesting that the protection of the host might be affected [33]. T cells recognize an antigenic peptide on an MHC molecule at the surface of an antigen-presenting cell (APC) (dendritic cell, monocyte, macrophage, B cell). This recognition is ensured by the T-cell receptor (TCR) whose binding site is composed of six small polypeptide loops: two CDR1 loops, two CDR2 loops, and two CDR3 loops. CDR1 and CDR2 loops bind the MHC molecule. CDR3 loops bind the peptide. This figure presents the frequency of hydrophobic, acid, basic and polar amino acids at each position within TCR CDR3 loops from murine pups conceived and born at 1 or 2 G.*

environment; 85% of the TCR repertoire was different in 2 G pups compared to control pups. Thus, the diversity of T-cell antigen receptor repertoire is significantly altered by 2 G exposure, which will likely affect host defense.

The impact of a model aiming at mimicking socio-environmental stresses experienced by astronauts [34] was then studied. This model involves the chronic exposure of mice to unpredictable socio-environmental stresses of various types (e.g., confinement, isolation, cage tilt, paired housing, perturbed circadian rhythm) and moderate intensity. It was demonstrated that this type of stressors only modifies 25% of the TCR repertoire [35]. Consequently, it appears that a change in the gravitational force has a much greater impact than socio-environmental stresses on the T-cell antigen receptor repertoire.
